# pos

id: cord-304623-j9ay4jkf
pos: NNP
token:
  https://www.pirbright.ac.uk/news/2019/11/bill-melinda-gates-foundation-funds-development-pirbright%E2%80%99s-livestock-antibody-hub

lemma:
  https://www.pirbright.ac.uk/news/2019/11/bill-melinda-gates-foundation-funds-development-pirbright%E2%80%99s-livestock-antibody-hub


id: cord-304623-j9ay4jkf
pos: ADD
token:
  https://portal.nifa.usda.gov/web/crisprojectpages/1016686-immune-reagents-for-ruminants-with-primary-focus-on-bovine-specific-reagents.html

lemma:
  https://portal.nifa.usda.gov/web/crisprojectpages/1016686-immune-reagents-for-ruminants-with-primary-focus-on-bovine-specific-reagents.html


id: cord-304623-j9ay4jkf
pos: NNP
token:
  http://www.vetvaccnet.ac.uk/publications/veterinaryimmunology-toolbox-meeting-uk-veterinary-vaccinologynetwork

lemma:
  http://www.vetvaccnet.ac.uk/publications/veterinaryimmunology-toolbox-meeting-uk-veterinary-vaccinologynetwork


id: cord-332150-j76726no
pos: NNP
token:
  https://investor.regeneron.com/newsreleases/news-release-details/regeneron-and-sanofi-provideupdate-us-phase-23-adaptive

lemma:
  https://investor.regeneron.com/newsreleases/news-release-details/regeneron-and-sanofi-provideupdate-us-phase-23-adaptive


id: cord-320474-jyk7zphp
pos: NNP
token:
  https://www.biospace.com/article/releases/i-mab-announcesind-clearance-from-fda-for-tjm2-to-treat-cytokine-release-syndrome-crsassociated-with-severe-coronavirus-disease-19-covid-19-/

lemma:
  https://www.biospace.com/article/releases/i-mab-announcesind-clearance-from-fda-for-tjm2-to-treat-cytokine-release-syndrome-crsassociated-with-severe-coronavirus-disease-19-covid-19-/


# ent

id: cord-003545-corvd5cs
type: PROTEIN
entity:
  actin 1 1 000 dilution anti ATG5 1 500 dilution anti LC3 1 1 000 dilution anti SGIV major capsid protein MCP 1 1 000 dilution anti RGNNV capsid protein CP 1 1


id: cord-003378-0ozhye9q
type: DNA
entity:
  polyclonal rabbit anti mouse Fgl2 antibody 1 100 Proteintech USA polyclonal rabbit anti mouse fibrinogen antibody 1 1 000 Abcam EngLand polyclonal rabbit antimouse Fas antibody 1 50 Abcam


id: cord-003378-0ozhye9q
type: DNA
entity:
  monoclonal mouse antihuman mouse Fgl2 1 750 Abnova a monoclonal mouse antihuman HBP1 1 100 Santa Cruz USA


id: cord-003378-0ozhye9q
type: CELL_LINE
entity:
  reverse 5 GCCA CCA CGC TCT TCT GT 3 mIL 1β forward 5 TGT AAT GAA AGA CGG CAC ACC 3 mIL 1β reverse 5 TCT TCT TTG GGT ATT GCT TGG 3 mFgl2 forward 5 GCC AAA TGT GAG TCC CTG GAA 3 mFgl2 reverse 5 TTC CAC CCA AGA GCA CGT TTA AG 3 hFgl2 forward 5 ACA GTT CAG GCT GGT GGT 3


id: cord-003378-0ozhye9q
type: ORG
entity:
  the Cell Institute of the Chinese Academy of Sciences Shanghai China Human Umbilical Vein Endothelial Cells


id: cord-004151-9815ikzg
type: PROTEIN
entity:
  nsp1 membrane rearrangement nsp2 and nsp3 replicative endonuclease nsp11 major virulence factors nsp3 8


id: cord-268781-6l74rrlm
type: DNA
entity:
  HLA A 11 01 positive individuals Influenza Research Database and Immune Epitope Database Peptide pulsed target groups


id: cord-265005-e6rpryrh
type: CHEMICAL
entity:
  IFN alpha beta IFN gamma and IFN lambda in host defense Suppressor of cytokine signaling 1 regulates the immune


id: cord-265855-zf52vl11
type: PROTEIN
entity:
  protein 3 RIG 1 retinoic acid inducible gene I MAVS Mitochondrial antiviral signaling protein TANK TRAF family member


id: cord-265855-zf52vl11
type: PROTEIN
entity:
  IRAK interleukin 1 receptor associated kinase TRAF 6 tumor necrosis factor receptor associated factor 6 TAK1 IKK I kappa B kinase NFκB nuclear factor kappa B A20 zinc protein PDE phosphodiesterase


id: cord-265855-zf52vl11
type: GGP
entity:
  Iκkε I kappa B kinase epsilon TBK1 TANK binding kinase 1 IRF3 interferon regulatory factor 3 TLR Toll


id: cord-265855-zf52vl11
type: GGP
entity:
  IRAK interleukin 1 receptor associated kinase TRAF 6 tumor necrosis factor receptor associated factor 6 TAK1 IKK I kappa B kinase NFκB nuclear factor kappa B A20 zinc protein PDE phosphodiesterase cGMP cyclic guanosine


id: cord-253108-p3wlw5d4
type: CELL_TYPE
entity:
  maternal antigen NK natural killer nTreg natural regulatory T cell PAP prostatic acid phosphatase TGF transforming growth factor Treg regulatory T cell Tregs nTreg 6


id: cord-001674-tp4o7fxx
type: DISEASE
entity:
  Bacillus subtilis signal peptide peptidase A Structure of signal peptide peptidase A with C termini bound in the active


id: cord-257662-viy65y72
type: WORK_OF_ART
entity:
  The Role of Myeloid Cell Activation and Arginine Metabolism in the Pathogenesis of Virus Induced Diseases


id: cord-003368-f8f2utzx
type: PROTEIN
entity:
  goat anti rabbit IgG H L antibody Cell Signaling Darmstadt Germany 1 5000 or goat anti mouse IgG H L antibody


id: cord-030803-6i0e2zkd
type: WORK_OF_ART
entity:
  A Framework of All Discovered Immunological Pathways and Their Roles for Four Specific Types of Pathogens and Hypersensitivities


id: cord-263141-n200x6z1
type: PROTEIN
entity:
  IFN inducible transmembrane proteins 1 2 and 3 4 MX1 proteins 5 and 2 5 oligoadenylate synthetase OAS RNAaseL system 6 Proinflammatory cytokines


id: cord-263141-n200x6z1
type: ORG
entity:
  Respiratory Antiviral Immunity and Immunobiotics Beneficial Effects on Inflammation Coagulation Interaction


id: cord-003122-a3f4l6iu
type: DISEASE
entity:
  influenza A virus genome packaging A distinct lineage of influenza A virus from bats New world bats harbor diverse influenza A viruses Crystal structures of two subtype N10 neuraminidase like proteins from bat influenza A viruses


id: cord-003091-uvfppirt
type: PROTEIN
entity:
  vascular endothelial growth factor 165 166 macrophage colony stimulating factor 167 transforming growth factor


id: cord-003091-uvfppirt
type: DISEASE
entity:
  cytomegalovirus dissemination Subcapsular sinus macrophages limit acute gammaherpesvirus dissemination


id: cord-259131-36udb7uc
type: DISEASE
entity:
  acutely infected animals Figure 2F Interestingly the percentage of IL 10 expressing AMs further decreased significantly


id: cord-259131-36udb7uc
type: DISEASE
entity:
  human immunodeficiency virus in the body The role of monocytes and macrophages in the pathogenesis of HIV 1 infection


id: cord-259131-36udb7uc
type: DISEASE
entity:
  HIV 1 infected human monocyte derived macrophages The binding epitopes of human CD16 Fc gamma RIII monoclonal antibodies Implications for ligand binding T cell exhaustion PD


id: cord-262673-j2ot35lt
type: CELL_TYPE
entity:
  intestinal epithelial cells 23 Club cells ciliated cells type I and type II alveolar cells 24 Ciliated epithelial cells


id: cord-003914-ss8vdpox
type: PROTEIN
entity:
  gp85 specific mouse monoclonal antibody 1 800 and fluorescein isothiocyanate FITC conjugated antimouse IgG secondary antibodies 1 5 000 Sigma Finally 3 10 4 cells


id: cord-257116-6td3efjw
type: DISEASE
entity:
  RSV infected airway epithelial cells RSV exposed monocytes and virus specific antibodies Newcastle disease


id: cord-268438-bjs5oliw
type: PROTEIN
entity:
  amino acids 1 187 zbRIG I 2CARD 188 937 zbRIG I 2CARD 812 927 zbRIG I RD and 188 811 zbRIG I 2CARD RD


id: cord-284156-btb4oodz
type: GGP
entity:
  Kaposi s sarcoma associated herpesvirusencoded deubiquitinase ORF64 Regulation of RIG I like receptor


id: cord-003825-tkqxb1ql
type: DNA
entity:
  anti CD4 IgG2b clone 74 12 4 WSU Monoclonal Antibody Center USA anti CD8 IgG2a clone 76 2 11 WSU USA


id: cord-262944-9k64f0tw
type: ORG
entity:
  the National Institutes for Health National Institute for Child Health and Development R01HD091218 to


id: cord-262944-9k64f0tw
type: ORG
entity:
  Human Placental Trophoblasts Confer Protection against Zika Virus Infection Selective Activation of Type II


id: cord-288496-7rrh2gg6
type: PROTEIN
entity:
  cord 288496 7rrh2gg6 authors Stryhn Anette Kongsgaard Michael Rasmussen Michael Harndahl Mikkel Nors


id: cord-288496-7rrh2gg6
type: CHEMICAL
entity:
  Mikkel Nors Østerbye Thomas Bassi Maria Rosaria Thybo Søren Gabriel Mette Hansen Morten Bagge Nielsen Morten Christensen


id: cord-020770-wpub7krf
type: PROTEIN
entity:
  Gpnmb Fabp5 Spp1 Igf1 Itgax Gm1673 Cst7 Cox6a2 Apoe Ch25h Clec7a Lilrb4 Csf1 Axl Lpl Sulf2 Egr2 Anxa5 Cd68 Timp2


id: cord-020770-wpub7krf
type: PROTEIN
entity:
  22 genes Ank Anxa5 Aplp2 Atp1a3 Clec7a Colec12 Csf1 Ephx1 Fabp5 Fam20c Gm1673 Gpnmb Hpse Igf1 Itgax Lilrb4 Lpl Nceh1 Plaur Pld3 Plin2


id: cord-020770-wpub7krf
type: CL
entity:
  amoeboid microglia 67 68 With the new notion of microglial phenotypes emerging these early amoeboid microglia


id: cord-020770-wpub7krf
type: CL
entity:
  microglial and macrophage responses after spinal cord injury Inflammation and brain injury acute cerebral ischaemia peripheral and central inflammation The far reaching scope of neuroinflammation after traumatic brain injury Recruitment of beneficial M2 macrophages


id: cord-282336-zvc04s39
type: CL
entity:
  epithelial endothelial barrier resulting in increased vascular permeability 2 Non cardiogenic pulmonary edema characterized by excessive accumulation of protein


id: cord-279105-e2zjxjox
type: WORK_OF_ART
entity:
  Portable Tests Come Online to Curb Coronavirus Pandemic Statement on Point of Care Serology Testing for SARS CoV 2


id: cord-267567-w39f584z
type: CHEMICAL
entity:
  hepatitis C virus non structural protein 2 Hepatitis C virus nonstructural 4B protein modulates sterol regulatory element binding protein signaling via the AKT pathway


id: cord-298604-tn8hc6jv
type: GGP
entity:
  neutrophil adhesion 8 8 fold 0 05 and trans endothelial migration 1 9 fold p 0 05 Hypoxia also increased


id: cord-261367-i1n8x0uc
type: PROTEIN
entity:
  biotin rat anti mouse IgE R35 118 BD Biosciences and streptavidin alkaline phosphatase Invitrogen Alkaline phosphate substrate


id: cord-261367-i1n8x0uc
type: PROTEIN
entity:
  donkey antigoat Alexa Flour R 568 rabbit fluorescein Alexa Fluor R 488 streptavidin Alexa Fluor R 555


id: cord-026866-0hlre9i6
type: WORK_OF_ART
entity:
  Prophylactic Activity of Orally Administered FliD Reactive Monoclonal SIgA Against Campylobacter Infection


id: cord-003598-m2fsrwvw
type: PROTEIN
entity:
  viral nonstructural 1 protein NS1 polymerase basic 1 protein PB1 polymerase basic 2 protein PB2 polymerase acidic PA


id: cord-255034-x100xo2t
type: GGP
entity:
  Pseudomonas aeruginosa alkaline protease and elastase Natural killer cells kill Burkholderia cepacia complex


id: cord-254809-o454k6ae
type: DISEASE
entity:
  influenza B virus parainfluenza virus 1 2 3 metapneumovirus common coronavirus Epstein Barr virus cytomegalovirus rhinovirus adenovirus and bocavirus


id: cord-256998-or73in8m
type: CELL_LINE
entity:
  BJMC3879 murine mammary adenocarcinomas CT26 murine colon adenocarcinomas and RENCA renal cell carcinomas


id: cord-256998-or73in8m
type: PROTEIN
entity:
  RheoSwitch Therapeutic System R RTS gene switch AdTCPmIL 12 Recombinant replication defective adenoviral vector expressing


id: cord-256998-or73in8m
type: PROTEIN
entity:
  trans retinoic acid Chimeric Antigen Receptor CBD Collagen Binding Domain CBD IL 12 Collagen binding immunocytokine


id: cord-256998-or73in8m
type: CELL_LINE
entity:
  mPEG MSCs Mesenchymal Stem Cells mscIL 12 her2 IgG3 Mouse single chain IL 12 fused Mesenchymal stem cells MSCs


id: cord-256998-or73in8m
type: CHEMICAL
entity:
  DMP cationic micelles 3 dimyristyloxypropyl N N dimethyl 2 hydroxyethyl ammonium bromide dioleoyl phosphatidylethanolamine


id: cord-280941-ds6x0yym
type: PROTEIN
entity:
  recombinant NPs hRID WT RBD FR hRID 2 m RBD FR hRID 9 m RBD FR hRID WT RBD SSG FR and FR and MERS CoV RBD protein


id: cord-283505-ousbar6c
type: CELL_LINE
entity:
  WEHI 24 Geelong VIC Australia anti CD8 PE clone OKT8 eBioscience CA USA anti GL7 AlexaFluor 647 clone GL7 BD Phamingen San Diego CA USA anti MHC II biotin clone CAT82A


id: cord-283505-ousbar6c
type: ORG
entity:
  the Commonwealth Scientific and Industrial Research Organization CSIRO Australian Center for Disease Prevention ACDP Animal Ethics Committee


id: cord-283505-ousbar6c
type: DISEASE
entity:
  influenza A H7N9 virus in primary human macrophages Cytokine and chemokine levels in patients infected with the novel avian influenza A H7N9 virus


id: cord-269222-g2ibmo75
type: DISEASE
entity:
  human immunodeficiency virus HIV herpes simplex virus HSV human papillomavirus and cytomegalovirus infection


id: cord-264814-v4wnmg03
type: PERSON
entity:
  Crawford Nigel W Giles Michelle Koirala Archana Macartney Kristine Russell Fiona Teh Benjamin W Wen Sophie CH title


id: cord-285760-y37ji92k
type: PROTEIN
entity:
  nucleocapsid protein NP V protein V phosphoprotein P matrix M protein fusion F protein small hydrophobic SH protein hemagglutininneuraminidase HN protein


id: cord-285760-y37ji92k
type: GPE
entity:
  the Russian Federation Routine Immunization Regional and Country Profiles Russian Federation Summary of Routine Immunization and Vaccine Preventable Diseases Surveillance Data


id: cord-285760-y37ji92k
type: ORG
entity:
  Routine Immunization Regional and Country Profiles Turkey Summary of Routine Immunization and Vaccine Preventable Diseases Surveillance Data


id: cord-280605-2i4gk7et
type: GGP
entity:
  Alzheimer s disease 219 rheumatoid arthritis 222 cardiovascular diseases 223 224 and cancer 225 among others Also recent studies propose that the activation of NFkB signaling pathways could be the main driver of these associations 226 227 228 229 Interestingly De Almeida et


id: cord-280605-2i4gk7et
type: WORK_OF_ART
entity:
  Unveiling the Role of Inflammation and Oxidative Stress on Age Related Cardiovascular Diseases NF kB Mediated Neuroinflammation


id: cord-280605-2i4gk7et
type: WORK_OF_ART
entity:
  Neuroprotective Effects of Endurance Exercise Against High Fat Diet Induced Hippocampal Neuroinflammation


id: cord-280605-2i4gk7et
type: DISEASE
entity:
  chronic obstructive pulmonary diseased human bronchial epithelial cells Acute respiratory distress syndrome


id: cord-278081-tk7vn1v1
type: GGP
entity:
  Alzheimer s disease pathogenetic role and potential use as biomarkers of disease progression Brain polyamine


id: cord-278081-tk7vn1v1
type: GGP
entity:
  Alzheimer s disease consequences for epigenetic regulation of rDNA and cognition The disappearing Barr body


id: cord-253862-jl1zhg13
type: TAXON
entity:
  human coronavirus OC43 HCoV OC43 human coronavirus HKU1 HCoV HKU1 Human coronavirus 229E HCoV 229E human coronavirus


id: cord-253862-jl1zhg13
type: DISEASE
entity:
  human coronavirus OC43 HCoV OC43 human coronavirus HKU1 HCoV HKU1 Human coronavirus 229E HCoV 229E human coronavirus NL63 HCoV NL63


id: cord-300429-b0zev8zb
type: CHEMICAL
entity:
  N terminal cysteine residue of hedgehog proteins sonic Indian and desert in mammals It determines secretion of these proteins


id: cord-300429-b0zev8zb
type: DISEASE
entity:
  acute respiratory syndrome virus the fusion F protein of paramyxoviruses e g measles virus Env of retroviruses e g HIV 1 feline immunodeficiency virus FIV


id: cord-300429-b0zev8zb
type: CHEMICAL
entity:
  Sindbis virus glycoproteins S acylation of the hemagglutinin of influenza viruses mass spectrometry reveals site specific attachment of stearic acid


id: cord-300429-b0zev8zb
type: DISEASE
entity:
  human immunodeficiency virus type 1 transmembrane protein gp41 harbors lipid raft association determinants Bioorthogonal


id: cord-295416-y3lvcjqd
type: PROTEIN
entity:
  CD206 C068C2 IL 5 TRFK5 IFNγ XMG1 2 Granzyme B QA16A02 Biolegend and IL 13 ebio13A ThermoFisher Scientific MA


id: cord-263433-oldy0gta
type: DISEASE
entity:
  influenza and VSV viruses SFV and HCV respectively We also thank Pablo Gastaminza for the HuH7 cells sensitive to HCV infection


id: cord-273505-pcsw3vmx
type: GGP
entity:
  toxins e g Enterococcus spp Haemophilus influenzae type b Streptococcus pyogenes Staphylococcus aureus cytomegalovirus


id: cord-273505-pcsw3vmx
type: DISEASE
entity:
  allogeneic haematopoietic stem cell transplant recipients Community acquired respiratory virus infections


id: cord-283382-t890r7xp
type: PROTEIN
entity:
  ChAd63 MVA ME TRAP vectored malaria vaccine candidate in 5 17 months old infants and children A prophylactic multivalent vaccine


id: cord-286337-qk90xb3a
type: CELL_TYPE
entity:
  gut helper T cell responses Respiratory influenza virus infection induces intestinal immune injury via microbiota mediated Th17 cell


id: cord-286337-qk90xb3a
type: GGP
entity:
  i e Streptococcus Prevotella Veillonella Streptococcus Haemophilus Neisseria Streptococcus Moraxella Haemophilus


id: cord-303017-4zx94rm6
type: WORK_OF_ART
entity:
  Can Beta 2 Adrenergic Pathway Be a New Target to Combat SARS CoV 2 Hyperinflammatory Syndrome Lessons Learned From Cancer


id: cord-303017-4zx94rm6
type: ORG
entity:
  Propranolol Attenuates Surgical Stress Induced Elevation of the Regulatory T Cell Response in Patients Undergoing Radical Mastectomy Perioperative COX 2


id: cord-295302-vwrxentv
type: CHEMICAL
entity:
  amino acid random peptide phage display library Ph D 7 New England Biolabs Conceptually this mimotope library


id: cord-297960-4x1j0iqg
type: PROTEIN
entity:
  CD44 antigen CD44 Serine arginine repetitive matrix protein 2 SRRM2 Myristoylated alaninerich C kinase substrate MARCKS BAG family molecular chaperone regulator 3 BAG3


id: cord-302295-nblmshni
type: TAXON
entity:
  virus encephalomyocarditis virus poliovirus coxsackievirus murine cytomegalovirus herpes simplex virus


id: cord-302295-nblmshni
type: WORK_OF_ART
entity:
  Targeting Toll Like Receptors Promising Therapeutic Strategies for the Management of Sepsis Associated Pathology and Infectious Diseases


id: cord-302295-nblmshni
type: DISEASE
entity:
  HBV HIV influenza virus Herpes simplex virus Epstein Barr virus vesicular stomatitis virus papilloma virus respiratory syncytial virus and Sendai virus


id: cord-284409-xiyeceib
type: WORK_OF_ART
entity:
  The Antibody Germline Maturation Hypothesis Elicitation of Broadly Neutralizing Antibodies Against HIV 1 and Cord Blood IgM Repertoires


id: cord-304626-ffao7vka
type: DNA
entity:
  human immunodeficiency virus Virus complement evasion strategies Complement and viral pathogenesis Viral


id: cord-308433-vrkdtrfz
type: CELL_LINE
entity:
  CD4 T cell monocyte cocultures 1 1 000 dilution in the presence or absence of TNF blockade After 6 days antigen stimulated CD4 T cells


id: cord-272491-a84pahdr
type: CL
entity:
  epithelial and endothelial regenerative properties However FIGURE 1 Potential effects of pharmaceutical preparations of MSC secretome on different organs involved in COVID 19 The MSC secretome in the form of conditioned medium containing extracellular vesicles EVs and mitochondria


id: cord-296585-yfh5d4io
type: PROTEIN
entity:
  inflammatory mediators interleukin IL 1β IL 6 IL 8 IL 33 C X C motif chemokine ligand CXCL 10 granulocyte macrophage colonystimulating factor GM CSF granulocyte colony stimulating factor G CSF tumor necrosis factor TNF


id: cord-296585-yfh5d4io
type: PROTEIN
entity:
  fibroblast growth factor 1 and 2 FGF1 2 transforming growth factor TGF β1 C C motif chemokine ligand CCL 2 CCL20


id: cord-296585-yfh5d4io
type: ORG
entity:
  the Physiographical Society Forssman s Foundation and Endowments for the Natural Sciences Medicine and Technology Skåne County Council


id: cord-319729-6lzjhn8j
type: ORG
entity:
  Lab Attenuated Rabies Virus Causes Abortive Infection and Induces Cytokine Expression in Astrocytes by


id: cord-321568-okvt1fg3
type: WORK_OF_ART
entity:
  Formulation and Evaluation of Naringenin Nanosuspensions for Bioavailability Enhancement Enantiomers


id: cord-320431-0877trhh
type: PROTEIN
entity:
  nuclear factor κB pathways Dangerassociated molecular patterns and danger signals in idiopathic pulmonary fibrosis Toll like receptors


id: cord-320431-0877trhh
type: GGP
entity:
  EGF receptor Ras Raf extracellular signalregulated kinase cascade and Sp1 13 and epidermal growth factor receptor


id: cord-320431-0877trhh
type: DISEASE
entity:
  asthmatic human airway Epidermal growth factor system regulates mucin production in airways Van Seuningen I


id: cord-333932-aqcllik0
type: PROTEIN
entity:
  human CD4 PerCP RPA T4 Biolegend CD8 APC SK1 BD Biosciences CD8 PE SK1 Biolegend PD 1 PE EH12 2H7 Biolegend


id: cord-278839-uu2wlpmp
type: DNA
entity:
  CD4 CD25 regulatory T cell compartment Viral infections during pregnancy The association between viral infections maternal and fetal mortality morbidity Intrauterine infection with varicellazoster virus after maternal varicella Preparing for influenza after 2009 H1N1 special considerations for pregnant women and newborns Pandemic 2009 influenza A H1N1 virus illness among pregnant women


id: cord-340228-mvqoyror
type: CELL_LINE
entity:
  MagNa Pure LC 2 0 system Roche Diagnostic Systems Branchburg NJ HSV 2 Keratitis 2 HPV 2 Warts 2 CMV 8 Viremia 4 Pneumonia 6 Adenovirus 3 Viremia 2 Pneumonia 1 Enterovirus 3 Hemophagocytosis 1 Viremia 1 Pneumonia 1 Norovirus 1


id: cord-340228-mvqoyror
type: ORG
entity:
  the Advancement of Sciences International Union of Immunological Societies 2017 Primary Immunodeficiency Diseases Committee Report


id: cord-340228-mvqoyror
type: DISEASE
entity:
  Cytomegalovirus CMV Epstein Barr virus EBV herpesvirus 6 HHV 6 adenovirus respiratory and gastrointestinal viruses


id: cord-328003-yovp8squ
type: WORK_OF_ART
entity:
  Structure Function and Antigenicity of the SARS CoV 2 Spike Glycoprotein SARS CoV 2 Vaccines Status Report Composition


id: cord-328003-yovp8squ
type: WORK_OF_ART
entity:
  Structural Modeling of SARS CoV 2 Spike Protein Reveals an Evolutionary Distinct and Proteolytically Sensitive Activation Loop


id: cord-328003-yovp8squ
type: WORK_OF_ART
entity:
  Tracking Changes in SARS CoV 2 Spike Evidence that D614G Increases Infectivity of the COVID 19 Virus


id: cord-351305-6vtv2xuh
type: PROTEIN
entity:
  CRP 125 9 mg L reference range 5 mg L procalcitonin 0 56 ng mL reference range 0 05 ng mL and interleukin 6 IL 6 320


id: cord-350492-1s6wtj25
type: PROTEIN
entity:
  inducible protein 10 IP 10 monocyte chemoattractant protein 1 MCP 1 macrophage inflammatory protein 1


id: cord-350492-1s6wtj25
type: PROTEIN
entity:
  viral RNA receptor retinoic acid inducible gene I 9 cytosolic receptor melanoma differentiation associated gene 5


id: cord-350492-1s6wtj25
type: PROTEIN
entity:
  adaptor molecule myeloid differentiation primary response 88 MyD88 transcription factor nuclear factor κB NF κB


id: cord-330417-8nnobx8g
type: PROTEIN
entity:
  proinflammatory cytokines interleukin 1 beta IL 1β IL 6 IL 8 IL 10 tumor necrosis factor alpha and IL 12 p70


id: cord-348283-7xorq5ce
type: DNA
entity:
  HLA DRB1 03 01 HLA DRB1 07 01 HLA DRB1 15 01 HLA DRB3 01 01 HLA DRB3 02 02 HLA DRB4 01 01 and HLA DRB5 01 01 Epitopes


id: cord-344610-mqq6fmsp
type: WORK_OF_ART
entity:
  The Dipeptidyl Peptidase Family Prolyl Oligopeptidase and Prolyl Carboxypeptidase in the Immune System and Inflammatory Disease Including Atherosclerosis


id: cord-346389-gbmnoo84
type: GGP
entity:
  IL 2 IL 7 IL 10 tumor necrosis factor α TNF α C X C motif chemokine 10 CXCL 10 monocyte chemoattractant protein 1 MCP 1


id: cord-341513-e6p3lrlf
type: GGP
entity:
  interleukin IL 1β IL 6 monocyte chemotactic protein 1 tumor necrosis factor alpha TNF α and chemokine C C motif ligand 5 6 7


id: cord-341513-e6p3lrlf
type: ORG
entity:
  the Research Ethics Committee of College of Veterinary Medicine Huazhong Agricultural University Hubei Wuhan China


id: cord-344093-3bniy5b5
type: CELL_TYPE
entity:
  alveolar epithelial cells lung macrophages IAV 5 7 10 RSV 137 Necrosis of fibroblasts dendritic cells


id: cord-344093-3bniy5b5
type: PROTEIN
entity:
  death domain TRAF TNF receptor associated protein JNK Janus kinase Bax Bcl 2 associated X protein c FLIP cellular FADD


id: cord-344093-3bniy5b5
type: GGP
entity:
  RIP kinase dependent necrosis enabling survival to mTOR inhibition Caspase mediated crosstalk between autophagy and apoptosis mutual adjustment or matter of


id: cord-344093-3bniy5b5
type: CHEMICAL
entity:
  alpha interferon in respiratory syncytial virus and human metapneumovirus experimental infections Pegylated interferon


id: cord-353594-z1vxamvp
type: PROTEIN
entity:
  anti PM Scl anti CNP B anti PCNA anti dsDNA anti nucleosome anti histone anti ribosomal Pprotein anti


id: cord-353594-z1vxamvp
type: WORK_OF_ART
entity:
  Clinical Serological and Histopathological Similarities Between Severe COVID 19 and Acute Exacerbation of Connective Tissue Disease Associated Interstitial Lung Disease


id: cord-353594-z1vxamvp
type: ORG
entity:
  the American College of Radiology and RSNA Secondary Publication Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease Autoantibodies


id: cord-291941-9a4tt4f7
type: WORK_OF_ART
entity:
  Understanding the Role of Mucosal Associated Invariant T Cells in Non human Primate Models of HIV Infection date


id: cord-320474-jyk7zphp
type: PROTEIN
entity:
  inflammatory cytokines interleukin IL 2 IL 7 granulocyte colony stimulating factor G CSF granulocyte monocyte stimulating factor GM CSF interferon


id: cord-320474-jyk7zphp
type: PROTEIN
entity:
  Janus kinase 2 JAK2 signal transducer and activator of transcription 5 STAT5 nuclear factor kappa light chain enhancer


id: cord-320474-jyk7zphp
type: PROTEIN
entity:
  immune response APC antigen presenting cell DC dendritic cell GM CSF granulocyte macrophage colony stimulating factor


id: cord-333041-69n2wwn3
type: GGP
entity:
  TNF α IL 6 IL 1β IL 8 IL 12 monocyte chemoattractant protein 1 MCP1 interferon gamma inducible protein IP10


id: cord-318418-uqxzds6g
type: GGP
entity:
  ppd7 5 14 vs 4 34 kg day milk produced by VP was significantly P 0 05 greater than that by VC Total immunoglobulin Ig A


id: cord-336924-7xcbtn3q
type: ORG
entity:
  the Antiphospholipid Syndrome Coagulation Abnormalities and Thrombosis in Patients Infected With SARS CoV 2


id: cord-312075-asbt0mcj
type: DNA
entity:
  2016 11 11 journal Front Immunol DOI 10 3389 fimmu 2016 00498 sha add093424f4f1c1da746abb3227193fb2fefbefa doc_id 312075 cord_uid asbt0mcj


id: cord-328763-hcbs20a0
type: PROTEIN
entity:
  intercellular adhesion molecule ICAM 1 vascular cell adhesion molecule VCAM 1 activated leucocyte cell adhesion molecule ALCAM


id: cord-328763-hcbs20a0
type: CELL_TYPE
entity:
  apoptotic cells 214 215 216 liposomes 217 extracellular vesicles 218 or nanoparticles 219 220 221 222 223


id: cord-328763-hcbs20a0
type: CL
entity:
  microglial phagocytic responses 89 133 These data indicate that M CSF plays an important role in ability of microglia to clear myelin


id: cord-354030-8tfg881h
type: PRODUCT
entity:
  I99 G100 C102 S103 M104 T105 D106 I107 A108 K109 K110 P111 T112 E113 T114 I115 C116 A117 P118 L119 T120 G125 R126 V127 D128 G129 V131 D132 L133 F134 R135 N136


id: cord-352150-ey9kc7zj
type: ORG
entity:
  Cross Reactivity of TCR Repertoire Current Concepts Challenges and Implication for Allotransplantation


id: cord-336201-fl606l3b
type: PROTEIN
entity:
  mannose binding lectin MBL surfactant protein D SP D dendritic cell specific intercellular adhesion molecule 3


id: cord-336201-fl606l3b
type: PROTEIN
entity:
  granulocyte colony stimulating factor G CSF macrophage inflammatory protein 1α MIP1α serum ferritin fibrinogen plasminogen C reactive protein CRP


id: cord-336201-fl606l3b
type: GGP
entity:
  antibioticresistant Escherichia coli Proteus spp Klebsiella spp coagulasenegative staphylococci Enterobacter


id: cord-354620-xf6glr2h
type: ORG
entity:
  the Committee of Experiment Operational Guidelines and Animal Welfare of Sichuan Agricultural University


id: cord-352230-8mazd3eu
type: DISEASE
entity:
  HIV 1 infection Tripterygium wilfordii 197 Bakuchiol phenolic isoprenoid Psoralea corylifolia L 199 Rupestonic acid sesquiterpene Artemisia rupestris L


id: cord-352230-8mazd3eu
type: CHEMICAL
entity:
  nelfinavir lopinavir kaempferol quercetin luteolin 7glucoside demethoxycurcumin naringenin apigenin 7 glucoside oleuropein curcumin catechin epicatechin gallate zingerol gingerol


id: cord-353887-f4yd7guj
type: PROTEIN
entity:
  protein 3 MKK Mitogen activated protein kinase kinase SMAD5 SMAD Family Member 5 RORγt retinoic acid receptor


id: cord-353887-f4yd7guj
type: PROTEIN
entity:
  orphan nuclear receptor gamma t STAT Signal transducer and activator of transcription TAK1 TGFβ activated kinase T bet T box transcription factor 21


id: cord-353887-f4yd7guj
type: GGP
entity:
  SARS CoV 2 3 4 20 Glucocorticoids exhibit pharmacologic effects at any therapeutically relevant dose through classic genomic


# url

id: cord-304623-j9ay4jkf
domain: www.pirbright.ac.uk
url:
  http://www.pirbright.ac.uk/news/2019/11/bill-melinda-gates-foundation-funds-development-pirbright%E2%80%99s-livestock-antibody-hub


id: cord-304623-j9ay4jkf
domain: portal.nifa.usda.gov
url:
  http://portal.nifa.usda.gov/web/crisprojectpages/1016686-immune-reagents-for-ruminants-with-primary-focus-on-bovine-specific-reagents.html


id: cord-332150-j76726no
domain: investor.regeneron.com
url:
  http://investor.regeneron.com/newsreleases/news-release-details/regeneron-and-sanofi-provideupdate-us-phase-23-adaptive


id: cord-320474-jyk7zphp
domain: www.biospace.com
url:
  http://www.biospace.com/article/releases/i-mab-announcesind-clearance-from-fda-for-tjm2-to-treat-cytokine-release-syndrome-crsassociated-with-severe-coronavirus-disease-19-covid-19-/


# bib

id: cord-000647-uofygmeu
title: CD8(+) T Cells in Leishmania Infections: Friends or Foes?
author: Stäger, Simona
date: 2012-01-24
txt: ./txt/cord-000647-uofygmeu.txt
cache: ./cache/cord-000647-uofygmeu.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342007/
doi: 10.3389/fimmu.2012.00005
summary:
  However, since CTLs have been www.frontiersin.org observed in various mouse models and also in human patients, a possible protective role for Leishmania-specific cytotoxic T cells should not be excluded. major infection became less important also because of the strong evidence that Th1 cells were the primary cells involved in mediating protection against cutaneous leishmaniasis (Reiner and Locksley, 1995; Louis et al., 1998; Sacks and Noben-Trauth, 2002) . Vaccination of humans with heat-killed Leishmania or recombinant parasite proteins has so far failed to induce long-term immunity and only recovery from natural or experimental infection has provided proper protection. Pilot studies in the murine model of VL have also demonstrated that adoptive transfer of antigen-specific CD8 + T cells (Polley et al., 2006) or reactivation of CD8 + T cell responses through a therapeutic vaccine (Joshi et al., 2009) results in the control of parasite growth.

abstract:
  Host protection against several intracellular pathogens requires the induction of CD8(+) T cell responses. CD8(+) T cells are potent effector cells that can produce high amounts of pro-inflammatory cytokines and kill infected target cells efficiently. However, a protective role for CD8(+) T cells during Leishmania infections is still controversial and largely depends on the infection model. In this review, we discuss the role of CD8(+) T cells during various types of Leishmania infections, following vaccination, and as potential immunotherapeutic targets.


id: cord-001674-tp4o7fxx
title: Alternative Antigen Processing for MHC Class I: Multiple Roads Lead to Rome
author: Oliveira, Cláudia C.
date: 2015-06-05
txt: ./txt/cord-001674-tp4o7fxx.txt
cache: ./cache/cord-001674-tp4o7fxx.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457021/
doi: 10.3389/fimmu.2015.00298
summary:
  An exception is the C-terminal peptide of the endoplasmic reticulum (ER)-membrane-spanning ceramide synthase Trh4 that is surprisingly liberated by the signal peptide peptidase (SPP), the proteolytic enzyme involved in cleaving leader sequences. This intramembrane proteolysis by SPP is thought to be important for the clearance of the ER membrane by removing small protein remnants anchored at FIGURE 1 | Classical and alternative pathways for MHC class I presentation. Furin-processed antigens targeted to the secretory route were presented by MHC class I at the cell surface and could elicit functional CD8 T-cell responses in vivo in a TAP-independent fashion (75, 81) . Autophagy mediates transporter associated with antigen processing-independent presentation of viral epitopes through MHC class I pathway A transporter associated with antigen-processing independent vacuolar pathway for the MHC class I-mediated presentation of endogenous transmembrane proteins

abstract:
  The well described conventional antigen-processing pathway is accountable for most peptides that end up in MHC class I molecules at the cell surface. These peptides experienced liberation by the proteasome and transport by the peptide transporter TAP. However, there are multiple roads that lead to Rome, illustrated by the increasing number of alternative processing pathways that have been reported during last years. Interestingly, TAP-deficient individuals do not succumb to viral infections, suggesting that CD8 T cell immunity is sufficiently supported by alternative TAP-independent processing pathways. To date, a diversity of viral and endogenous TAP-independent peptides have been identified in the grooves of different MHC class I alleles. Some of these peptides are not displayed by normal TAP-positive cells and we therefore called them TEIPP, for “T-cell epitopes associated with impaired peptide processing.” TEIPPs are hidden self-antigens, are derived from normal housekeeping proteins, and are processed via unconventional processing pathways. Per definition, TEIPPs are presented via TAP-independent pathways, but recent data suggest that part of this repertoire still depend on proteasome and metalloprotease activity. An exception is the C-terminal peptide of the endoplasmic reticulum (ER)-membrane-spanning ceramide synthase Trh4 that is surprisingly liberated by the signal peptide peptidase (SPP), the proteolytic enzyme involved in cleaving leader sequences. The intramembrane cleaving SPP is thereby an important contributor of TAP-independent peptides. Its family members, like the Alzheimer’s related presenilins, might contribute as well, according to our preliminary data. Finally, alternative peptide routing is an emerging field and includes processes like the unfolded protein response, the ER-associated degradation, and autophagy-associated vesicular pathways. These data convince us that there is a world to be discovered in the field of unconventional antigen processing.


id: cord-003091-uvfppirt
title: Dendritic Cells in the Cross Hair for the Generation of Tailored Vaccines
author: Gornati, Laura
date: 2018-06-27
txt: ./txt/cord-003091-uvfppirt.txt
cache: ./cache/cord-003091-uvfppirt.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030256/
doi: 10.3389/fimmu.2018.01484
summary:
  Taking advantage of new adjuvants, innovative ags-delivery carriers and targeting strategies, it is now feasible to optimize the activation and ag presentation processes by the specific DCs subset that is the most effective in the initiation of the adaptive response needed in a given context. Indeed, MF59, an oil-in-water emulsion adjuvant, that allows long-lasting ag retention in draining LN and enhanced ag uptake by LN-resident DCs, promotes robust humoral responses via follicular DC activation (43) and CD4 + T cell immunity induction (44) . In addition to the use of NPs, targeting DC-specific receptors has become an attractive strategy for vaccine development due to the enforced efficiency of immune responses when compared to generic-delivering approaches. Moreover, vaccines based on the filamentous bacteriophage fd presenting an αDEC-205 scFv, efficiently induce DCs maturation via the activation of the TLR9-MyD88 pathway (144) , without adjuvants and further elicit potent antitumor responses when compared to non-tailored ag delivery (145) .

abstract:
  Vaccines represent the discovery of utmost importance for global health, due to both prophylactic action to prevent infections and therapeutic intervention in neoplastic diseases. Despite this, current vaccination strategies need to be refined to successfully generate robust protective antigen-specific memory immune responses. To address this issue, one possibility is to exploit the high efficiency of dendritic cells (DCs) as antigen-presenting cells for T cell priming. DCs functional plasticity allows shaping the outcome of immune responses to achieve the required type of immunity. Therefore, the choice of adjuvants to guide and sustain DCs maturation, the design of multifaceted vehicles, and the choice of surface molecules to specifically target DCs represent the key issues currently explored in both preclinical and clinical settings. Here, we review advances in DCs-based vaccination approaches, which exploit direct in vivo DCs targeting and activation options. We also discuss the recent findings for efficient antitumor DCs-based vaccinations and combination strategies to reduce the immune tolerance promoted by the tumor microenvironment.


id: cord-003122-a3f4l6iu
title: Influenza A Virus Cell Entry, Replication, Virion Assembly and Movement
author: Dou, Dan
date: 2018-07-20
txt: ./txt/cord-003122-a3f4l6iu.txt
cache: ./cache/cord-003122-a3f4l6iu.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062596/
doi: 10.3389/fimmu.2018.01581
summary:
  The segmentation of the influenza genome makes these additional trafficking requirements especially challenging, as each viral RNA (vRNA) gene segment must navigate the network of cellular membrane barriers during the processes of entry and assembly. To accomplish this goal, influenza A viruses (IAVs) utilize a combination of viral and cellular mechanisms to coordinate the transport of their proteins and the eight vRNA gene segments in and out of the cell. Influenza A viruses (IAVs) and type B viruses (IBVs) contain 8, negative-sense, single-stranded viral RNA (vRNA) gene segments ( Figure 1A ) (3, 4) , which encode transcripts for 10 essential viral proteins, as well as several strain-dependent accessory proteins ( Figure 1B) . In contrast to the early steps in IAV entry, vRNP trafficking to the nucleus following the fusion event is highly dependent on the host cell machinery and transport pathways [reviewed in Ref.

abstract:
  Influenza viruses replicate within the nucleus of the host cell. This uncommon RNA virus trait provides influenza with the advantage of access to the nuclear machinery during replication. However, it also increases the complexity of the intracellular trafficking that is required for the viral components to establish a productive infection. The segmentation of the influenza genome makes these additional trafficking requirements especially challenging, as each viral RNA (vRNA) gene segment must navigate the network of cellular membrane barriers during the processes of entry and assembly. To accomplish this goal, influenza A viruses (IAVs) utilize a combination of viral and cellular mechanisms to coordinate the transport of their proteins and the eight vRNA gene segments in and out of the cell. The aim of this review is to present the current mechanistic understanding for how IAVs facilitate cell entry, replication, virion assembly, and intercellular movement, in an effort to highlight some of the unanswered questions regarding the coordination of the IAV infection process.


id: cord-003319-u88gznxq
author: Huang, Weishan
date: 2018-11-19
txt: ./txt/cord-003319-u88gznxq.txt
cache: ./cache/cord-003319-u88gznxq.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252342/
doi: 10.3389/fimmu.2018.02625
summary:
  To determine whether co-expression of LAG3 and CD49b is exclusive to Foxp3 − Tr1 cell subset, we infected IL-10 GFP /Foxp3 RFP dual reporter mice with Nb, and analyzed the IL-10-producing T cells. Along with the model of parasitic infection shown in Figure 2 , our data suggest that co-expression of LAG3 and CD49b marks all IL-10-producing T cell lineages in the pulmonary system, and relative abundance of the marked T cell subsets is dependent on the type of immune response as shown in the disease models. Despite the shared feature of co-expression of LAG3 and CD49b by IL-10-producing Foxp3 + CD4 + , Foxp3 − CD4 + , and CD8 + T cells, we also observed interesting discrepancies in the proportional composition of these three IL-10 high T cell subsets that are all LAG3/CD49b double positive in the lung mucosa of different pulmonary inflammatory disease models, as well as in different anatomical locations in the same mice upon TCR activation in vivo.

title:
  Beyond Type 1 Regulatory T Cells: Co-expression of LAG3 and CD49b in IL-10-Producing T Cell Lineages

abstract:
  Type 1 regulatory CD4(+) T (Tr1) cells express high levels of the immunosuppressive cytokine IL-10 but not the master transcription factor Foxp3, and can suppress inflammation and promote immune tolerance. In order to identify and obtain viable Tr1 cells for research and clinical applications, co-expression of CD49b and LAG3 has been proposed as a unique surface signature for both human and mouse Tr1 cells. However, recent studies have revealed that this pattern of co-expression is dependent on the stimulating conditions and the differentiation stage of the CD4(+) T cells. Here, using an IL-10(GFP)/Foxp3(RFP) dual reporter transgenic murine model, we demonstrate that co-expression of CD49b and LAG3 is not restricted to the Foxp3(−) Tr1 cells, but is also observed in Foxp3(+) T regulatory (Treg) cells and CD8(+) T cells that produce IL-10. Our data indicate that IL-10-producing Tr1 cells, Treg cells and CD8(+) T cells are all capable of co-expressing LAG3 and CD49b in vitro following differentiation under IL-10-inducing conditions, and in vivo following pathogenic insult or infection in the pulmonary mucosa. Our findings urge caution in the use of LAG3/CD49b co-expression as sole markers to identify Tr1 cells, since it may mark IL-10-producing T cell lineages more broadly, including the Foxp3(−) Tr1 cells, Foxp3(+) Treg cells, and CD8(+) T cells.


id: cord-003368-f8f2utzx
title: A Functionally Different Immune Phenotype in Cattle Is Associated With Higher Mastitis Incidence
author: Lutterberg, Karina
date: 2018-12-06
txt: ./txt/cord-003368-f8f2utzx.txt
cache: ./cache/cord-003368-f8f2utzx.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291514/
doi: 10.3389/fimmu.2018.02884
summary:
  After in vitro stimulation of peripheral blood derived lymphocytes (PBL), we detected distinctly deviant expression levels of several master regulators of immune responses in BNP cells, pointing to a changed immune phenotype with severe dysregulation of immune response in BNP cows. As other authors claimed the possibility of a genetic predisposition of BNP dams for production of BNP inducing alloantibodies (22) (23) (24) , our studies focused on investigating a general difference in immune responses between PregSure BVD vaccinated control cows and BNP donors. In in vitro proliferation assays with T cell mitogen ConA we observed that 22% of the unvaccinated cows reacted similar to BNP dams by showing a hyperproliferative reaction to ConA (immune deviant (ID) phenotype; Figure 6A , reaction difference ID to controls or BNP to controls, * * * * p < 0.0001).

abstract:
  A novel vaccine against bovine viral diarrhea (BVD) induced pathogenic antibody production in 5–10% of BVD-vaccinated cows. Transfer of these antibodies via colostrum caused Bovine neonatal pancytopenia (BNP) in calves, with a lethality rate of 90%. The exact immunological mechanisms behind the onset of BNP are not fully understood to date. To gain further insight into these mechanisms, we analyzed the immune proteome from alloreactive antibody producers (BNP cows) and non-responders. After in vitro stimulation of peripheral blood derived lymphocytes (PBL), we detected distinctly deviant expression levels of several master regulators of immune responses in BNP cells, pointing to a changed immune phenotype with severe dysregulation of immune response in BNP cows. Interestingly, we also found this response pattern in 22% of non-BVD-vaccinated cows, indicating a genetic predisposition of this immune deviant (ID) phenotype in cattle. We additionally analyzed the functional correlation of the ID phenotype with 10 health parameters and 6 diseases in a retrospective study over 38 months. The significantly increased prevalence of mastitis among ID cows emphasizes the clinical relevance of this deviant immune response and its potential impact on the ability to fight infections.


id: cord-003378-0ozhye9q
author: Yu, Haijing
date: 2018-12-13
txt: ./txt/cord-003378-0ozhye9q.txt
cache: ./cache/cord-003378-0ozhye9q.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300492/
doi: 10.3389/fimmu.2018.02935
summary:
  In vitro, CC10 was found to significantly inhibit the expression of Fgl2 in IFN-γ-treated THP-1 cells and MHV-3-infected mouse peritoneal macrophages by western blot and real-time PCR. Our study found that Fgl2 was highly expressed in peripheral blood mononuclear cells (PBMCs) and in liver tissue of humans or mice with severe viral hepatitis, and was positively related to the severity of the disease (13, 14) . Compared to wild-type mice, CC10-knockout mice exhibited excessive airway inflammation Abbreviations: FH, fulminant hepatitis; MHV-3, murine hepatitis virus strain 3; Fgl2, Fibrinogen-like protein 2; CC10, Clara cell 10 KDa protein; ALF, acute liver failure; PFU, plaque-forming units; PBS, phosphate-buffered saline; ALT, alanine aminotransferase; AST, aspartate aminotransferase; PCA, pro-coagulant activity; HRP, horseradish peroxidase; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling. In this study, we investigated the role of CC10 in hepatitis virus strain 3 (MHV-3)-induced FH in mice and explored whether CC10 protein could regulate Fgl2 in the disease process.

title:
  Clara Cell 10 kDa Protein Alleviates Murine Hepatitis Virus Strain 3-Induced Fulminant Hepatitis by Inhibiting Fibrinogen-Like Protein 2 Expression

abstract:
  Background: Fulminant hepatitis (FH) is a serious threat to human life, accompanied by massive and rapid necroinflammation. Kupffer cells, the major immune cell population involved in innate immune responses, are considered to be central for FH. Fibrinogen-like protein 2 (Fgl2) is a pro-coagulant protein that is substantially induced in macrophages upon viral infection, and Fgl2 depletion represses murine hepatitis virus strain 3 (MHV-3) infection. Clara cell 10 kDa (CC10) protein is a secretory protein with anti-inflammatory properties in allergic rhinitis and asthma. However, its mechanisms of action and pathogenic roles in other disease are still unclear. In this study, we aimed to determine the role of CC10 in FH and the regulation of Fgl2 by CC10. Methods: A mouse FH model was established by peritoneal injection of MHV-3. The mice received CC10 protein through tail vein injection before viral infection. Survival rate, liver function, liver histology, fibrin deposition, and necrosis were examined. The regulatory effect of CC10 on Fgl2 expression was investigated using THP-1 cells and mouse peritoneal macrophages in vitro. Results: In the mouse FH model induced by MHV-3, the survival rate increased from 0 to 12.5% in the CC10 group compared to that in the saline-only control group. Meanwhile, the levels of ALT and AST in serum were significantly decreased and liver damage was reduced. Furthermore, hepatic Fgl2, TNF-α, and IL-1β expression was obviously downregulated together with fibrin deposition, and hepatocyte apoptosis was reduced after administration of CC10 protein. In vitro, CC10 was found to significantly inhibit the expression of Fgl2 in IFN-γ-treated THP-1 cells and MHV-3-infected mouse peritoneal macrophages by western blot and real-time PCR. However, there was no direct interaction between CC10 and Fgl2 as shown by co-immunoprecipitation. Microarray investigations suggested that HMG-box transcription factor 1 (HBP1) was significantly low in CC10-treated and IFN-γ-primed THP-1 cells. HBP1-siRNA treatment abrogated the inhibitory effect of CC10 on Fgl2 expression in Human Umbilical Vein Endothelial cells (HUVECs). Conclusion:CC10 protects against MHV-3-induced FH via suppression of Fgl2 expression in macrophages. Such effects may be mediated by the transcription factor HBP1.


id: cord-003545-corvd5cs
author: Li, Chen
date: 2019-03-19
txt: ./txt/cord-003545-corvd5cs.txt
cache: ./cache/cord-003545-corvd5cs.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433989/
doi: 10.3389/fimmu.2019.00517
summary:
  The transcription level of EcAtg5 was significantly increased in cells infected with red-spotted grouper nervous necrosis virus (RGNNV). Further studies showed that overexpression EcAtg5 activated autophagy, decreased expression levels of interferon related cytokines or effectors and pro-inflammatory factors, and inhibited the activation of nuclear factor κB, IFN-sensitive response element, and IFNs. In addition, ectopic expression of EcAtg5 affected cell cycle progression by hindering the G1/S transition. Taken together, our results demonstrated that fish Atg5 exerted a crucial role in virus replication by promoting autophagy, down-regulating antiviral IFN responses, and affecting the cell cycle. To analyze the gene expression profiles in response to different viral infections, the transcription levels of EcAtg5 were examined in RGNNV or SGIV infected cells. The results showed that EcAtg5 plays crucial roles in virus replication via promoting autophagy, down-regulating antiviral IFN responses, and affecting cell cycle.

title:
  Fish Autophagy Protein 5 Exerts Negative Regulation on Antiviral Immune Response Against Iridovirus and Nodavirus

abstract:
  Autophagy is an important biological activity that maintains homeostasis in eukaryotic cells. However, little is known about the functions of fish autophagy-related genes (Atgs). In this study, we cloned and characterized Atg5, a key gene in the autophagy gene superfamily, from orange-spotted grouper (Epinephelus coioides) (EcAtg5). EcAtg5 encoded a 275-amino acid protein that shared 94 and 81% identity to seabass (Lates calcarifer) and humans (Homo sapiens), respectively. The transcription level of EcAtg5 was significantly increased in cells infected with red-spotted grouper nervous necrosis virus (RGNNV). In cells infected with Singapore grouper iridovirus (SGIV), EcAtg5 expression declined during the early stage of infection and increased in the late stage. Fluorescence microscopy revealed that EcAtg5 mainly localized with a dot-like pattern in the cytoplasm of grouper cells. Overexpression of EcAtg5 significantly increased the replication of RGNNV and SGIV at different levels of detection, as indicated by increased severity of the cytopathic effect, transcription levels of viral genes, and levels of viral proteins. Knockdown of EcAtg5 decreased the replication of RGNNV and SGIV. Further studies showed that overexpression EcAtg5 activated autophagy, decreased expression levels of interferon related cytokines or effectors and pro-inflammatory factors, and inhibited the activation of nuclear factor κB, IFN-sensitive response element, and IFNs. In addition, ectopic expression of EcAtg5 affected cell cycle progression by hindering the G1/S transition. Taken together, our results demonstrated that fish Atg5 exerted a crucial role in virus replication by promoting autophagy, down-regulating antiviral IFN responses, and affecting the cell cycle.


id: cord-003598-m2fsrwvw
title: Response Modifiers: Tweaking the Immune Response Against Influenza A Virus
author: Elbahesh, Husni
date: 2019-04-12
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473099/
doi: 10.3389/fimmu.2019.00809
abstract:
  Despite causing pandemics and yearly epidemics that result in significant morbidity and mortality, our arsenal of options to treat influenza A virus (IAV) infections remains limited and is challenged by the virus itself. While vaccination is the preferred intervention strategy against influenza, its efficacy is reduced in the elderly and infants who are most susceptible to severe and/or fatal infections. In addition, antigenic variation of IAV complicates the production of efficacious vaccines. Similarly, effectiveness of currently used antiviral drugs is jeopardized by the development of resistance to these drugs. Like many viruses, IAV is reliant on host factors and signaling-pathways for its replication, which could potentially offer alternative options to treat infections. While host-factors have long been recognized as attractive therapeutic candidates against other viruses, only recently they have been targeted for development as IAV antivirals. Future strategies to combat IAV infections will most likely include approaches that alter host-virus interactions on the one hand or dampen harmful host immune responses on the other, with the use of biological response modifiers (BRMs). In principle, BRMs are biologically active agents including antibodies, small peptides, and/or other (small) molecules that can influence the immune response. BRMs are already being used in the clinic to treat malignancies and autoimmune diseases. Repurposing such agents would allow for accelerated use against severe and potentially fatal IAV infections. In this review, we will address the potential therapeutic use of different BRM classes to modulate the immune response induced after IAV infections.


id: cord-003656-7mzsaz7a
title: DNA Vaccines Against Mycoplasma Elicit Humoral Immune Responses in Ostriches
author: Wium, Martha
date: 2019-05-14
txt: ./txt/cord-003656-7mzsaz7a.txt
cache: ./cache/cord-003656-7mzsaz7a.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527592/
doi: 10.3389/fimmu.2019.01061
summary:
  Currently there are no commercially available vaccines against ostrich-infecting mycoplasmas and this study therefore set out to develop and evaluate the use of a DNA vaccine against mycoplasma infections in ostriches using an OppA protein as antigen. The ability of the DNA vaccines to elicit an anti-OppA antibody response was evaluated by ELISA using the recombinant OppA protein of Ms03 as coating antigen. In this study we report, for the first time, that a DNA vaccine can elicit a humoral immune response in ostriches using OppA as antigen. The controls were serum samples representing the week 0, 3, 6, and 9 sampling points of a single ostrich, randomly selected from the pCI-neo_oppA 1,200 µg group based on high titers produced after vaccination. In this study, DNA vaccines were developed for ostriches using the oppA gene of an ostrich-infecting mycoplasma (Ms03) as vaccine antigen.

abstract:
  In ostriches, the population densities resulting from intensive rearing increases susceptibility to pathogens such as mycoplasmas. In addition to good management practices, vaccination offers an attractive alternative for controlling mycoplasma infections in food animals, instead of using antibiotics, which often leave unacceptable residues. The use of live attenuated vaccines, however, carry the concern of reversion to virulence or genetic recombination with field strains. Currently there are no commercially available vaccines against ostrich-infecting mycoplasmas and this study therefore set out to develop and evaluate the use of a DNA vaccine against mycoplasma infections in ostriches using an OppA protein as antigen. To this end, the oppA gene of “Mycoplasma nasistruthionis sp. nov.” str. Ms03 was cloned into two DNA vaccine expression vectors after codon correction by site-directed mutagenesis. Three-months-old ostriches were then vaccinated intramuscularly at different doses followed by a booster vaccination after 6 weeks. The ability of the DNA vaccines to elicit an anti-OppA antibody response was evaluated by ELISA using the recombinant OppA protein of Ms03 as coating antigen. A statistically significant anti-OppA antibody response could be detected after administration of a booster vaccination indicating that the OppA protein was successfully immunogenic. The responses were also both dose and vector dependent. In conclusion, the DNA vaccines were able to elicit an immune response in ostriches and can therefore be viewed as an option for the development of vaccines against mycoplasma infections.


id: cord-003685-jcvrqeew
title: Acute Phase Proteins in Marine Mammals: State of Art, Perspectives and Challenges
author: Gelain, Maria Elena
date: 2019-05-29
txt: ./txt/cord-003685-jcvrqeew.txt
cache: ./cache/cord-003685-jcvrqeew.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549532/
doi: 10.3389/fimmu.2019.01220
summary:
  The APPs have demonstrated their role as early markers of inflammation in veterinary medicine, thus several APPs were tested in marine mammals, such as C-reactive protein (CRP), serum amyloid-A (SAA), and Haptoglobin (Hp). To examine the humoral response, species-specific antibodies against IgG were produced and used to evaluate serum IgG levels in killer whale by radial immunodiffusion assay (41) and by competitive ELISA in bottlenose dolphins (42, 43) . Serum total protein analysis were used to assess health status in several cetaceans species such as pantropical spotted dolphins (Stenella attenuata) (48), beluga (49) , minke whales (Balaenoptera acutorostrata) (50) and killer whales (51) as well as in other marine mammals, like harbor seals (Phoca vitulina) (52) and walruses (Odobenus rosmarus) (53) . The availability of sensitive markers of inflammation both for free-ranging and managed marine mammals is nowadays considered fundamental to evaluate the health status and, in rehabilitation setting, to monitor the response to therapy and to define the prognosis.

abstract:
  The term “acute phase response” (APR) is referred to a nonspecific and complex reaction of an organism that occurs shortly after any tissue damage, such as infection, trauma, neoplasia, inflammation, and stress. The APR can be identified and monitored with some laboratory tests, such as the concentration of several plasma proteins, the acute phase proteins (APPs). The APPs are components of the non-specific innate immune response, and their plasma concentration is proportional to the severity and/or the extent of tissue damage. The evaluation of health status of marine mammals is difficult because the classical clinical signs of illness used for human and domestic animals are difficult to recognize and understand. For this reason, in the past years, several efforts were done to identify laboratory markers of disease in these animals. The APPs have demonstrated their role as early markers of inflammation in veterinary medicine, thus several APPs were tested in marine mammals, such as C-reactive protein (CRP), serum amyloid-A (SAA), and Haptoglobin (Hp). However, the difficulty to extrapolate the knowledge about APPs in one species to another, the lack of specie-specific reagents, the absence of data about negative APPs have hampered their extent use in marine mammals. Herein, the state of art of APPs in marine mammals is reviewed, with particular attention to pre-analytical and analytical factors that should be taken into account in validation and interpretation of APPs assays. Moreover, the current application, potential utility and the future developments of APPs in marine mammals is highlighted and discussed.


id: cord-003724-705h5l06
title: Identification of a Novel Non-desmoglein Autoantigen in Pemphigus Vulgaris
author: Di Lullo, Giulia
date: 2019-06-19
txt: ./txt/cord-003724-705h5l06.txt
cache: ./cache/cord-003724-705h5l06.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593111/
doi: 10.3389/fimmu.2019.01391
summary:
  Pemphigus vulgaris (PV) is an autoimmune bullous disease of the skin and mucous membranes characterized by the presence of circulating and tissue-bound autoantibodies against keratinocyte cell surface antigens, specifically desmoglein (Dsg) 1 and 3. The existence of both pathogenic and non-pathogenic anti-Dsg autoAbs has recently been underscored by isolation of human monoclonal antibodies (hMabs) from pemphigus patients. Then, considering that previous studies demonstrated the ability of intact autoAbs to enter living cells (8, 16, 17) , we addressed the potential pathogenicity of α-catenin-specific Mab PVF144 by evaluating its acantholytic activity in an in vitro keratinocyte dissociation assay. Further studies are needed: (i) to evaluate whether PVF144 may act synergistically with anti-Dsg antibodies using more informative approaches, such as in vitro organ culture or in vivo models; (ii) to assess the possible role of anti-α-catenin autoAbs in pemphigus initiation and evolution in vivo; and (iii) to characterize this novel antigen as a possible target of epitope spreading phenomena in PV.

abstract:
  Pemphigus vulgaris (PV) is an autoimmune bullous disease of the skin and mucous membranes characterized by the presence of circulating and tissue-bound autoantibodies against keratinocyte cell surface antigens, specifically desmoglein (Dsg) 1 and 3. The pathogenic role of anti-Dsg antibodies is well-established, while the mechanism of blister formation is only partly defined. We have applied a previously developed method for the efficient immortalization of IgG+ memory B cells to identify novel target antigens in PV. A human monoclonal antibody reactive with a hitherto unreported non-Dsg antigen was isolated. Immunoprecipitation and immunoblotting studies with keratinocyte extracts indicated α-catenin as the putative antigen, then confirmed by immunoblotting on the recombinant protein. Four of ten PV sera reacted with recombinant α-catenin. Although the isolated human monoclonal antibody was per se unable to dissociate keratinocyte monolayers and also to synergize with a pathogenic antibody in vitro, further studies are warranted to assess its possible in vivo contribution in the multifactorial pathogenesis and heterogeneous manifestations of PV disease.


id: cord-003825-tkqxb1ql
author: Toman, Miroslav
date: 2019-08-06
txt: ./txt/cord-003825-tkqxb1ql.txt
cache: ./cache/cord-003825-tkqxb1ql.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691355/
doi: 10.3389/fimmu.2019.01689
summary:
  The goals of our study were to compare the immune response to different killed and modified live vaccines against PRRS virus and to monitor the antibody production and the cell mediated immunity both at the systemic and local level. The goals of our study were to compare the immune response to different killed and modified live vaccines against PRRS virus and to monitor the antibody production and the cell mediated immunity both at the systemic and local level. Twenty-one days after the final vaccination, all piglets, including the control non-immunized group (C5), were i.n., infected with the Lelystad strain of PRRS virus. Twenty-one days after the final vaccination, all piglets, including the control non-immunized group (C5), were i.n., infected with the Lelystad strain of PRRS virus. Comparison of serum and oral fluid antibody responses after vaccination with modified live (MLV) porcine reproductive and respiratory syndrome virus (PRRSV) vaccine in PRRS endemic farms

title:
  Dynamics and Differences in Systemic and Local Immune Responses After Vaccination With Inactivated and Live Commercial Vaccines and Subsequent Subclinical Infection With PRRS Virus

abstract:
  The goals of our study were to compare the immune response to different killed and modified live vaccines against PRRS virus and to monitor the antibody production and the cell mediated immunity both at the systemic and local level. In the experiment, we immunized four groups of piglets with two commercial inactivated (A1—Progressis, A2—Suivac) and two modified live vaccines (B3—Amervac, B4—Porcilis). Twenty-one days after the final vaccination, all piglets, including the control non-immunized group (C5), were i.n., infected with the Lelystad strain of PRRS virus. The serum antibody response (IgM and IgG) was the strongest in group A1 followed by two MLV (B3 and B4) groups. Locally, we demonstrated the highest level of IgG antibodies in bronchoalveolar lavages (BALF), and saliva in group A1, whereas low IgA antibody responses in BALF and feces were detected in all groups. We have found virus neutralization antibody at DPV 21 (days post vaccination) and higher levels in all groups including the control at DPI 21 (days post infection). Positive antigen specific cell-mediated response in lymphocyte transformation test (LTT) was observed in groups B3 and B4 at DPV 7 and in group B4 at DPV 21 and in all intervals after infection. The IFN-γ producing lymphocytes after antigen stimulation were found in CD4(−)CD8(+) and CD4(+)CD8(+) subsets of all immunized groups 7 days after infection. After infection, there were obvious differences in virus excretion. The virus was detected in all groups of piglets in serum, saliva, and occasionally in feces at DPI 3. Significantly lower virus load was found in groups A1 and B3 at DPI 21. Negative samples appeared at DPI 21 in B3 group in saliva. It can be concluded that antibodies after immunization and infection, and the virus after infection can be detected in all the compartments monitored. Immunization with inactivated vaccine A1—Progressis induces high levels of antibodies produced both systemically and locally. Immunization with MLV-vaccines (Amervac and Porcilis) produces sufficient antibody levels and also cell-mediated immunity. After infection virus secretion gradually decreases in group B3, indicating tendency to induce sterile immunity.


id: cord-003828-bhfghcby
title: Vaccination in Multiple Sclerosis: Friend or Foe?
author: Zrzavy, Tobias
date: 2019-08-07
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693409/
doi: 10.3389/fimmu.2019.01883
abstract:
  Multiple sclerosis (MS) is a debilitating disease of the central nervous systems (CNS). Disease-modifying treatments (including immunosuppressive treatments) have shown positive effects on the disease course, but are associated with systemic consequences on the immune system and may increase the risk of infections and alter vaccine efficiency. Therefore, vaccination of MS patients is of major interest. Over the last years, vaccine hesitancy has steadily grown especially in Western countries, partly due to fear of sequelae arising from vaccination, especially neurological disorders. The interaction of vaccination and MS has been discussed for decades. In this review, we highlight the immunology of vaccination, provide a review of literature and discuss the clinical consideration of MS, vaccination and immunosuppression. In conclusion, there is consensus that MS cannot be caused by vaccines, neither by inactivated nor by live vaccines. However, particular attention should be paid to two aspects: First, in immunocompromised patients, live vaccines may lead to a stronger immune reaction with signs of the disease against which the patients have been vaccinated, albeit in weakened form. Second, protection provided by vaccination should be controlled in patients who have been vaccinated while receiving immunomodulatory or immunosuppressive treatment. In conclusion, there is evidence that systemic infections can worsen MS, thus vaccination will lower the risk of relapses by reducing the risk of infections. Therefore, vaccination should be in general recommended to MS patients.


id: cord-003914-ss8vdpox
author: Wang, Shenghua
date: 2019-10-02
txt: ./txt/cord-003914-ss8vdpox.txt
cache: ./cache/cord-003914-ss8vdpox.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783503/
doi: 10.3389/fimmu.2019.02299
summary:
  title: Oral Immunization of Chickens With Recombinant Lactobacillus plantarum Vaccine Against Early ALV-J Infection plantarum) containing the gp85 protein was explored, and the effects of this vaccine on the prevention of subgroup J Avian Leukosis Virus (ALV-J) infection were assessed. plantarum group showed a significant rise in antibody levels after inoculation, and provide improved protection against ALV-J according to viremia detection. The ALV-J-NX0101 strain, pMD18T-env recombinant vector (containing the gp85 gene), gp85-specific mouse monoclonal anti-body (MAb JE9), ALV-J antibody test kit, and ALV P27 antigen enzyme-linked immunosorbent assay (ELISA) test kits (IDEXX USA Inc., Beijing, China) were donated by Prof. plantarum significantly triggered specific IgG and IgA antibodies against ALV-J, and enhanced the levels of IgG and sIgA compared to the control group (Figures 4, 5) . This study described the mucosal and systemic immune responses specific to ALV-J induced by an orally administered recombinant L.

title:
  Oral Immunization of Chickens With Recombinant Lactobacillus plantarum Vaccine Against Early ALV-J Infection

abstract:
  In this study, a novel oral vaccine of recombinant Lactobacillus plantarum (L. plantarum) containing the gp85 protein was explored, and the effects of this vaccine on the prevention of subgroup J Avian Leukosis Virus (ALV-J) infection were assessed. In the current study, the gp85 protein of ALV-J was expressed on the surface of L. plantarum with the surface-display motif, pgsA, by constructing a shuttle vector pMG36e:pgsA:gp85. Surface localization of the fusion protein was verified by western blotting and flow cytometry. Subsequently, Specific Pathogen Free Hy-Line Brown layer chickens were orally vaccinated with the recombinant L. plantarum and presented with high levels of serum immunoglobulin G (IgG) and secretory immunoglobulin A (sIgA) titers in bile and duodenal-mucosal fluid. After challenged with ALV-J of a 3 × 10(3) 50% tissue culture infective dose (TCID50), serum samples of the chickens were collected and viremia was analyzed. Results showed that, compared to the L. plantarum and PBS control group, the recombinant L. plantarum group showed a significant rise in antibody levels after inoculation, and provide improved protection against ALV-J according to viremia detection. These results indicate that oral immunization with the recombinant L. plantarum provided an effective means for eliciting protective immune response against early ALV-J infection.


id: cord-004151-9815ikzg
author: Pan, Xiaocheng
date: 2020-01-08
txt: ./txt/cord-004151-9815ikzg.txt
cache: ./cache/cord-004151-9815ikzg.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960135/
doi: 10.3389/fimmu.2019.02995
summary:
  To investigate CTL epitope applications in swine, SLA-1(*)1502-restricted peptide epitopes matching porcine reproductive and respiratory syndrome virus (PRRSV) strains were explored by crystallography, biochemistry, and the specific pathogen-free (SPF) swine experiments. Next, the potential SLA-1(*)1502-restricted peptide epitopes matching four typical genetic PRRSV strains were identified based on the peptide-binding motif of SLA-1(*)1502 determined by structural analysis and alanine scanning of the NSP9-TMP9 peptide. In an attempt to identify anti-PRRSV CTL epitopes in this study, first, predicted peptide epitopes derived from PRRSV were synthesized, and a trimolecular complex, the structure of the epitope from PRRSV-NSP9 (TMPPGFELY, termed NSP9-TMP9)-bound SLA-1 * 1502 (pSLA-1 * 1502), was solved. The purified complex (44 kDa) of pSLA-1 * 1502 with the NSP9-TMP9 peptide (amino acid sequence TMPPGFELY, derived from residues 198-206 of the PRRSV non-structural protein) was dialyzed against crystallization buffer (20 mM Tris-HCl pH 8.0, 50 mM NaCl) and concentrated to 12 mg/mL.

title:
  Illumination of PRRSV Cytotoxic T Lymphocyte Epitopes by the Three-Dimensional Structure and Peptidome of Swine Lymphocyte Antigen Class I (SLA-I)

abstract:
  To investigate CTL epitope applications in swine, SLA-1(*)1502-restricted peptide epitopes matching porcine reproductive and respiratory syndrome virus (PRRSV) strains were explored by crystallography, biochemistry, and the specific pathogen-free (SPF) swine experiments. First, nine predicted PRRSV peptides were tested by assembly of the peptide-SLA-1(*)1502 (pSLA-1(*)1502) complexes, and the crystal structure of the SLA-1(*)1502 complex with one peptide (NSP9-TMP9) was determined. The NSP9-TMP9 peptide conformation presented by pSLA-1(*)1502 is different from that of the peptides presented by the known pSLA-1(*)0401 and pSLA-3(*)hs0202 complexes. Two consecutive Pro residues make the turn between P3 and P4 of NSP9-TMP9 much sharper. The D pocket of pSLA-1(*)1502 is unique and is important for peptide binding. Next, the potential SLA-1(*)1502-restricted peptide epitopes matching four typical genetic PRRSV strains were identified based on the peptide-binding motif of SLA-1(*)1502 determined by structural analysis and alanine scanning of the NSP9-TMP9 peptide. The tetrameric complex of SLA-1(*)1502 and NSP9-TMP9 was constructed and examined. Finally, taking NSP9-TMP9 as an example, the CTL immunogenicity of the identified PRRSV peptide epitope was evaluated. The SPF swine expressing the SLA-1(*)1502 alleles were divided into three groups: modified live vaccine (MLV), MLV+NSP9-TMP9, and the blank control group. NSP9-TMP9 was determined as a PRRSV CTL epitope with strong immunogenicity by flow cytometry and IFN-γ expression. Our study developed an integrated approach to identify SLA-I-restricted CTL epitopes from various important viruses and is helpful in designing and applying effective peptide-based vaccines for swine.


id: cord-004477-qu2o2iu1
title: Editorial: Porcine Anti-Viral Immunity
author: Vlasova, Anastasia N.
date: 2020-03-06
txt: ./txt/cord-004477-qu2o2iu1.txt
cache: ./cache/cord-004477-qu2o2iu1.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067899/
doi: 10.3389/fimmu.2020.00399
abstract: nan
summary:
  Immediately following viral infection, neonatal survival depends on innate immunity and passive protection by lactogenic immune factors such as pathogen-specific antibodies, until an adaptive immune response can develop. Wide-spread porcine reproductive and respiratory syndrome virus (PRRSV) and swine influenza virus (SIV) represent major health challenges in the large US swine production systems and possibly worldwide. In introducing the topic of anti-viral immunity, we emphasize the genetic diversity of viruses, the virus life cycle and the pathology that viral infection can cause. A more tedious procedure is to use only parts of the virus as the vaccine (subunit vaccines) that target the immune response to those viral epitopes that elicit VN antibodies. A second approach to vaccine development is use of live attenuated virus that has been genetically modified or cell culture adapted and cannot produce a disease in the host but can still replicate.


id: cord-015254-xtox2rxs
author: Li, Hao-Ling
date: 2020-03-20
txt: ./txt/cord-015254-xtox2rxs.txt
cache: ./cache/cord-015254-xtox2rxs.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098954/
doi: 10.3389/fimmu.2020.00477
summary:
  We modeled neuropathic pain in rats by inducing chronic constriction injury (CCI) of the sciatic nerve and analyzed the effects on C-X-C motif chemokine 10 (CXCL10)/CXCR3 activation, BSCB permeability, and immune cell migration from the circulation into the spinal cord. In this study, we examined the integrity of the BSCB and the migration of circulating immune cells into the spinal cord after chronic constriction injury (CCI) of the sciatic nerve, which induces neuropathic pain. To the best of our knowledge, it is the first study to report that blocking CXCL10/CXCR3 signaling attenuates the increases in BSCB permeability and T cell infiltration of the spinal cord induced by peripheral nerve injury. Previous studies have indicated that increased BSCB permeability is a prerequisite for immune cell infiltration of the spinal cord during the development of neuropathic pain (41) , and we found that blocking CXCL10/CXCR3 signaling with anti-CXCL10 antibodies reduced the BSCB''s permeability to NaFlu, which suggests that CXCL10/CXCR3 signaling plays a critical role in CCI-induced BSCB dysfunction.

title:
  C-X-C Motif Chemokine 10 Contributes to the Development of Neuropathic Pain by Increasing the Permeability of the Blood–Spinal Cord Barrier

abstract:
  Neuropathic pain is among the most debilitating forms of chronic pain. Studies have suggested that chronic pain pathogenesis involves neuroimmune interactions and blood–spinal cord barrier (BSCB) disruption. However, the underlying mechanisms are poorly understood. We modeled neuropathic pain in rats by inducing chronic constriction injury (CCI) of the sciatic nerve and analyzed the effects on C-X-C motif chemokine 10 (CXCL10)/CXCR3 activation, BSCB permeability, and immune cell migration from the circulation into the spinal cord. We detected CXCR3 expression in spinal neurons and observed that CCI induced CXCL10/CXCR3 activation, BSCB disruption, and mechanical hyperalgesia. CCI-induced BSCB disruption enabled circulating T cells to migrate into the spinal parenchyma. Intrathecal administration of an anti-CXCL10 antibody not only attenuated CCI-induced hyperalgesia, but also reduced BSCB permeability, suggesting that CXCL10 acts as a key regulator of BSCB integrity. Moreover, T cell migration may play a critical role in the neuroimmune interactions involved in the pathogenesis of CCI-induced neuropathic pain. Our results highlight CXCL10 as a new potential drug target for the treatment of nerve injury–induced neuropathic pain.


id: cord-020770-wpub7krf
author: Benmamar-Badel, Anouk
date: 2020-04-03
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147523/
doi: 10.3389/fimmu.2020.00430
title:
  Protective Microglial Subset in Development, Aging, and Disease: Lessons From Transcriptomic Studies

abstract:
  Microglial heterogeneity has been the topic of much discussion in the scientific community. Elucidation of their plasticity and adaptability to disease states triggered early efforts to characterize microglial subsets. Over time, their phenotypes, and later on their homeostatic signature, were revealed, through the use of increasingly advanced transcriptomic techniques. Recently, an increasing number of these “microglial signatures” have been reported in various homeostatic and disease contexts. Remarkably, many of these states show similar overlapping microglial gene expression patterns, both in homeostasis and in disease or injury. In this review, we integrate information from these studies, and we propose a unique subset, for which we introduce a core signature, based on our own research and reports from the literature. We describe that this subset is found in development and in normal aging as well as in diverse diseases. We discuss the functions of this subset as well as how it is induced.


id: cord-026866-0hlre9i6
author: Perruzza, Lisa
date: 2020-06-09
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296071/
doi: 10.3389/fimmu.2020.01011
title:
  Prophylactic Activity of Orally Administered FliD-Reactive Monoclonal SIgA Against Campylobacter Infection

abstract:
  Campylobacter infection is one of the most common causes of bacterial gastroenteritis worldwide and a major global health threat due to the rapid development of antibiotic resistance. Currently, there are no vaccines approved to prevent campylobacteriosis, and rehydration is the main form of therapy. Secretory immunoglobulin A (SIgA) is the main antibody class found in mucous secretions, including human milk, and serves as the first line of defense for the gastrointestinal epithelium against enteric pathogens. In this study, we describe the prophylactic activity of orally delivered recombinant SIgA generated from two human monoclonal antibodies (CAA1 and CCG4) isolated for their reactivity against the flagellar-capping protein FliD, which is essential for bacteria motility and highly conserved across Campylobacter species associated with severe enteritis. In an immunocompetent weaned mouse model, a single oral administration of FliD-reactive SIgA CAA1 or CCG4 at 2 h before infection significantly enhances Campylobacter clearance at early stages post-infection, reducing the levels of inflammation markers associated with epithelial damage and polymorphonuclear (PMN) cells infiltration in the cecum lamina propria. Our data indicate that the prophylactic activity of CAA1 and CCG4 is not only dependent on the specificity to FliD but also on the use of the SIgA format, as the immunoglobulin G (IgG) versions of the same antibodies did not confer a comparable protective effect. Our work emphasizes the potential of FliD as a target for the development of vaccines and supports the concept that orally administered FliD-reactive SIgA can be developed to prevent or mitigate the severity of Campylobacter infections as well as the development of post-infection syndromes.


id: cord-030385-btf502ju
author: Sun, Zhiheng
date: 2020-07-22
txt: ./txt/cord-030385-btf502ju.txt
cache: ./cache/cord-030385-btf502ju.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387432/
doi: 10.3389/fimmu.2020.01591
summary:
  However, it has not been clarified whether β-glucan-induced trained immunity causes different responses to early sepsis between male and female mice. The changes of inflammatory cytokines expression, and macrophage polarization in male, female, and ovariectomized C57BL/6 mice in sepsis model were investigated. Macrophage polarization toward the M1 phenotype, which exhibited enhanced trained immunity, was related to the difference in sepsis resistance between female and male mice. Mechanistically, we found that E2 inhibited the nuclear translocation of RelB, which is a member of non-canonical pathway of NFκB and contributes to macrophage polarization to change the intensity of trained immunity. Our results showed that females expressed higher IL-6 and TNFα than males in sepsis, and trained immunity exacerbated this trend (Figures 1I,J) . The in vitro trained immunity model was established with RAW264.7 and J774 ( Figure 5C ) cell lines derived from male and female mice, respectively.

title:
  17β-Estradiol Promotes Trained Immunity in Females Against Sepsis via Regulating Nucleus Translocation of RelB

abstract:
  Sepsis is more common among males than females, and the unequal estrogen levels have been suspected to play a vital role in gender differences. Recently, trained immunity is reported to be a novel strategy for the innate immune system to fight infection. However, it has not been clarified whether β-glucan-induced trained immunity causes different responses to early sepsis between male and female mice. In this study, sepsis was induced in mice by intraperitoneal injection of Escherichia coli (E. coli). The changes of inflammatory cytokines expression, and macrophage polarization in male, female, and ovariectomized C57BL/6 mice in sepsis model were investigated. For in vitro studies, different macrophages were treated with LPS. The function of estradiol (E2) on macrophage cell lines was verified and the mechanism of E2 affecting trained immunity was explored. We demonstrated that β-glucan-induced trained immunity was more resistant to sepsis in female than male mice. Macrophage polarization toward the M1 phenotype, which exhibited enhanced trained immunity, was related to the difference in sepsis resistance between female and male mice. Moreover, ovariectomized (OVX) mice manifested serious sepsis consequences with a weaker trained immunity effect than female mice. Female bone marrow-derived macrophages (BMDMs) were also apt to be polarized to the M1 phenotype in response to trained immunity in vitro. Furthermore, E2 promoted trained immunity in macrophage cell lines J774 and RAW264.7. E2 was also verified to facilitate trained immunity in primary BMDMs from female and male mice. Mechanistically, we found that E2 inhibited the nuclear translocation of RelB, which is a member of non-canonical pathway of NFκB and contributes to macrophage polarization to change the intensity of trained immunity. This study is the first to indicate the role of E2 in the trained immunity induced by β-glucan to protect against E. coli-induced sepsis via the non-canonical NFκB pathway. These results improve our understanding of the molecular mechanisms governing trained immunity in gender differences.


id: cord-030803-6i0e2zkd
author: Hu, Wan-Chung
date: 2020-08-07
txt: ./txt/cord-030803-6i0e2zkd.txt
cache: ./cache/cord-030803-6i0e2zkd.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426516/
doi: 10.3389/fimmu.2020.01992
abstract: nan
summary:
  STAT5a and STAT5b have distinct target genes in immune responses (15) , and STAT5b is the transcription factor that induces Tfh. Tfh can induce B-cells to produce IgM antibodies and IL-21 produced by Tfh facilitates B cell isotype switching to IgG (16, 17) . Type 2 myeloid dendritic cells (CD141+ mDC2) are the antigen presenting cells Eradicable immune responses include TH1, TH2, TH17, and THαβ. Initiation of eradicable immunity also requires innate lymphoid cells to produce the initial cytokines that drive different immunological pathways. THαβ immune responses against self-antigens present as type 2 antibody-dependent cytotoxic hypersensitivity, such as the acute stage of myasthenia gravis or Graves'' disease (37) . The effector cells of TH1-like immune responses include suppressive macrophages (M2), ILC1, suppressive CD8 T cells (CD28-CD8+Treg), IgA1producing B-cells, iNKT1 cells, and IFN-γ-/TGF-β-producing CD4 T cells (24, 40, 56) . TH3 immune responses induce type 2 antibody-dependent cytotoxic hypersensitivity, including the chronic stage of Systemic Lupus Erythematosus (SLE) (69) .

title:
  A Framework of All Discovered Immunological Pathways and Their Roles for Four Specific Types of Pathogens and Hypersensitivities


id: cord-032953-qy4b2l2f
author: Picard-Sánchez, Amparo
date: 2020-09-11
txt: ./txt/cord-032953-qy4b2l2f.txt
cache: ./cache/cord-032953-qy4b2l2f.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516018/
doi: 10.3389/fimmu.2020.581361
summary:
  title: Passive Immunization Delays Disease Outcome in Gilthead Sea Bream Infected With Enteromyxum leei (Myxozoa), Despite the Moderate Changes in IgM and IgT Repertoire The results showed that, fish injected with parasite-specific antibodies (spAbs) became infected with the parasite, but showed lower disease signs and intensity of infection than the other groups, indicating a later establishment of the parasite. 1 https://www.genome.jp/tools-bin/clustalw To study the IgM and IgT repertoire in the fish used as serum donors for passive immunization, cDNA from anterior intestine of SUR and NAI donor fish were used as template in PCR amplifications for each primer combination (F + R). Thus, we studied the IgM and IgT repertoire in the GSB that acted as SUR and NAI serum donors for the passive immunization trial. The repertoire analysis was performed on the anterior intestine, as previous studies revealed that in this particular organ IgM and IgT transcript expression increased upon re-exposure to the parasite in resistant fish (29) .

title:
  Passive Immunization Delays Disease Outcome in Gilthead Sea Bream Infected With Enteromyxum leei (Myxozoa), Despite the Moderate Changes in IgM and IgT Repertoire

abstract:
  Passive immunization constitutes an emerging field of interest in aquaculture, particularly with the restrictions for antibiotic use. Enteromyxum leei is a myxozoan intestinal parasite that invades the paracellular space of the intestinal epithelium, producing a slow-progressing disease, leading to anorexia, cachexia and mortalities. We have previously demonstrated that gilthead sea bream (GSB, Sparus aurata) that survive E. leei infection become resistant upon re-exposure, and this resistance is directly related to the presence of high levels of specific IgM in serum. Thus, the current work was aimed to determine if passive immunization could help to prevent enteromyxosis in GSB and to study in detail the nature of these protective antibodies. Serum from a pool of resistant (SUR) or naïve (NAI) animals was intracoelomically injected 24 h prior to the E. leei-effluent challenge and at 9 days post-challenge (dpc). Effluent challenge lasted for 23 days, and then the injected groups were allocated in separate tanks with clean water. A non-lethal parasite diagnosis was performed at 56 dpc. At the final sampling (100 dpc), blood, serum and tissues were collected for histology, molecular diagnosis and the detection of circulating antibodies. In parallel, we performed an immunoglobulin repertoire analysis of the fish generating SUR and NAI sera. The results showed that, fish injected with parasite-specific antibodies (spAbs) became infected with the parasite, but showed lower disease signs and intensity of infection than the other groups, indicating a later establishment of the parasite. Repertoire analysis revealed that E. leei induced a polyclonal expansion of diverse IgM and IgT subsets that could be in part an evasion strategy of the parasite. Nonetheless, GSB was able to produce sufficient levels of parasite-spAbs to avoid re-infection of surviving animals and confer certain degree of protection upon passive transfer of antibodies. These results highlight the crucial role of spAb responses against E. leei and set the basis for the development of effective treatment or prophylactic methods for aquaculture.


id: cord-033488-du8heorx
author: Ho, Thuong Thi
date: 2020-09-16
txt: ./txt/cord-033488-du8heorx.txt
cache: ./cache/cord-033488-du8heorx.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524870/
doi: 10.3389/fimmu.2020.02152
summary:
  (A) Sera from five mice from each group immunized with a negative control (wild-type crude extract, G1) or a positive control (commercial vaccine, G2) or the crude extract containing COE-GCN4pII (G3) were mixed, diluted 200 times and used as a primary antibody for detecting 1 µg of purified PEDV antigen. Different levels of PEDV-specific IgG (B), IgA (C), and IgM (D) antibodies in each mouse sera group were calculated as the reciprocal of the geometric mean titer of the five mice of each group vaccinated with the negative control (wild-type crude extract, G1) or the positive control (commercial vaccine, G2) or the crude extract containing COE-GCN4pII (G3). Therefore, plant crude extract containing the trimeric COE protein had the level of IgG antibodies similar to that of commercial vaccines against the PEDV DR13 strain after the third injection. Therefore, we concluded that plant crude extract containing the trimeric COE protein had a strong immunogenicity and induced a neutralizing antibody titer similar to that of the commercial vaccine against the attenuated PEDV DR13 strain.

title:
  Plant-Derived Trimeric CO-26K-Equivalent Epitope Induced Neutralizing Antibodies Against Porcine Epidemic Diarrhea Virus

abstract:
  Porcine epidemic diarrhea virus (PEDV) is a causative agent of a highly infectious disease with a high mortality rate, especially in newborn piglets in Asian countries resulting in serious economic loss. The development of a rapid, safe, effective and cost-efficient vaccine is crucial to protect pigs against PEDV infection. The COE antigen is regarded to be a major target for subunit vaccine development against PEDV infection. The naturally assembled COE protein forms a homotrimeric structure. In the present study, we successfully produced a trimeric COE protein as a native structure by fusion with the C-terminal isoleucine zipper trimerization (GCN4pII) motif in Nicotiana benthamiana, with a high expression level shown via semi-quantified Western blots. Trimeric COE protein was purified via immobilized metal affinity chromatography (IMAC), and its trimeric structure was successfully demonstrated by a cross-linking reaction, and a native PAGE gel. A crude extract containing the COE trimer was used for evaluating immunogenicity in mice. After 1 and 2 booster immunizations, the crude extract containing trimeric COE elicited elevated PEDV-specific humoral responses, as demonstrated by ELISA and Western blot analyses. Notably, a virus-neutralizing antibody assay indicated that the neutralization activities of sera of mice vaccinated with the crude extract containing COE-GCN4pII were similar to those of mice vaccinated with a commercial vaccine. These results suggest that crude extract containing trimeric COE is a promising plant-based subunit vaccine candidate for PEDV prevention.


id: cord-034310-izpt032p
author: Chernomordik, Fernando
date: 2020-10-06
txt: ./txt/cord-034310-izpt032p.txt
cache: ./cache/cord-034310-izpt032p.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573569/
doi: 10.3389/fimmu.2020.575577
summary:
  Furthermore, studies in apoE−/− mice suggest that T cells reactive to mCRAMP are functionally active in atherosclerosis and may be involved in modulating plaque calcification. Given the role of anti-microbial peptides as potential selfantigens in atherosclerosis, and the possible association with acute events, we tested if the cleaved fragment of hCAP-18, the cationic antimicrobial peptide LL-37, would induce differential T cell immune responses in patients with ACS. In this study, we showed that: (a) LL-37 stimulation of PBMCs from patients with ACS induced the persistence of CD8+ TEM cell response compared to patients with stable CAD or selfreported controls; (b) Immunization of apoE−/− mice with mCRAMP, the cationic fragment of CRAMP, increased CD8 CM T cell activation and cytolytic activity; and (c) Adoptive transfer of T cells from mice immunized with mCRAMP was associated with smaller atherosclerotic aortic plaque area, and absence of aortic sinus plaque calcification.

title:
  The Role of T Cells Reactive to the Cathelicidin Antimicrobial Peptide LL-37 in Acute Coronary Syndrome and Plaque Calcification

abstract:
  The human cationic anti-microbial peptide LL-37 is a T cell self-antigen in patients with psoriasis, who have increased risk of cardiovascular events. However, the role of LL-37 as a T cell self-antigen in the context of atherosclerosis remains unclear. The objective of this study was to test for the presence of T cells reactive to LL-37 in patients with acute coronary syndrome (ACS). Furthermore, the role of T cells reactive to LL-37 in atherosclerosis was assessed using apoE−/− mice immunized with the LL-37 mouse ortholog, mCRAMP. Peripheral blood mononuclear cells (PBMCs) from patients with ACS were stimulated with LL-37. PBMCs from stable coronary artery disease (CAD) patients or self-reported subjects served as controls. T cell memory responses were analyzed with flow cytometry. Stimulation of PBMCs with LL-37 reduced CD8+ effector T cell responses in controls and patients with stable CAD but not in ACS and was associated with reduced programmed cell death protein 1 (PDCD1) mRNA expression. For the mouse studies, donor apoE−/− mice were immunized with mCRAMP or adjuvant as controls, then T cells were isolated and adoptively transferred into recipient apoE−/− mice fed a Western diet. Recipient mice were euthanized after 5 weeks. Whole aortas and hearts were collected for analysis of atherosclerotic plaques. Spleens were collected for flow cytometric and mRNA expression analysis. Adoptive transfer experiments in apoE−/− mice showed a 28% reduction in aortic plaque area in mCRAMP T cell recipient mice (P < 0.05). Fifty six percent of adjuvant T cell recipient mice showed calcification in atherosclerotic plaques, compared to none in the mCRAMP T cell recipient mice (Fisher’s exact test P = 0.003). Recipients of T cells from mice immunized with mCRAMP had increased IL-10 and IFN-γ expression in CD8+ T cells compared to controls. In conclusion, the persistence of CD8+ effector T cell response in PBMCs from patients with ACS stimulated with LL-37 suggests that LL-37-reactive T cells may be involved in the acute event. Furthermore, studies in apoE−/− mice suggest that T cells reactive to mCRAMP are functionally active in atherosclerosis and may be involved in modulating plaque calcification.


id: cord-252568-b8sbvy0g
author: Marques Neto, Lázaro Moreira
date: 2017-03-08
txt: ./txt/cord-252568-b8sbvy0g.txt
cache: ./cache/cord-252568-b8sbvy0g.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/28337198/
doi: 10.3389/fimmu.2017.00239
summary:
  There is evidence that these particles display adjuvant characteristics, promoting cell recruitment, antigen-presenting cell activation, cytokine production, and inducing a humoral immune response. However, many NPs have been shown to stimulate immune responses, including cell recruitment, activation of antigen (Ag)-presenting cells (APCs), and induction of cytokine and chemokine release. Among the vaccines targeting extracellular bacteria and toxin, two were formulated with lipopolysaccharide (LPS) in glycopeptide Ag. The use of glycoantigen and LPS can trigger an intense response through TLR4 and B cell receptor activation; the presence of gold NPs (AuNPs) may have minimal influence on this response. To understand the possible uses of MeNPs as platforms for vaccines against infectious diseases, analysis is needed of the impact of different physicochemical characteristics of NPs on the innate immune response (Figure 1) .

title:
  Role of Metallic Nanoparticles in Vaccinology: Implications for Infectious Disease Vaccine Development

abstract:
  Subunit vaccines are safer but less immunogenic than live-attenuated vaccines or whole cell inactivated vaccines. Adjuvants are used to enhance and modulate antigen (Ag) immunogenicity, aiming to induce a protective and long-lasting immune response. Several molecules and formulations have been studied for their adjuvanticity, but only seven have been approved to formulate human vaccines. Metallic nanoparticles (MeNPs), particularly those containing gold and iron oxides, are widely used in medicine for diagnosis and therapy and have been used as carriers for drugs and vaccines. However, little is known about the immune response elicited by MeNPs or about their importance in the development of new vaccines. There is evidence that these particles display adjuvant characteristics, promoting cell recruitment, antigen-presenting cell activation, cytokine production, and inducing a humoral immune response. This review focuses on the characteristics of MeNPs that could facilitate the induction of a cellular immune response, particularly T-helper 1 and T-helper 17, and their potential functions as adjuvants for subunit vaccines.


id: cord-253108-p3wlw5d4
title: Interleukin 35: A Key Mediator of Suppression and the Propagation of Infectious Tolerance
author: Olson, Brian M.
date: 2013-10-18
txt: ./txt/cord-253108-p3wlw5d4.txt
cache: ./cache/cord-253108-p3wlw5d4.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2013.00315
doi: 10.3389/fimmu.2013.00315
summary:
  Following more than a decade of studies aimed at elucidating the mechanisms that mediate Treg activity, interest was rekindled in the mid-1990s with the transformational research of Sakaguchi and colleagues, who specifically identified a population of CD4+CD25+ T cells that had suppressive function, which were coined as naturally occurring thymic-derived Tregs, or natural Abbreviations: APC, antigen-presenting cell; DC, dendritic cell; EAE, experimental autoimmune encephalitis; Ebi3, Epstein-Barr virus-induced gene 3; IL, interleukin; iTreg, induced regulatory T cell; NIMA, non-inherited maternal antigen; NK, natural killer; nTreg, natural regulatory T cell; PAP, prostatic acid phosphatase; TGF, transforming growth factor; Treg, regulatory T cell. When activated in these conditions, iTregs gain potent suppressive functions, inhibiting T-cell proliferation and effector functions in an antigen non-specific fashion, and play a central role in mediating regulation and propagating infectious tolerance in a variety of malignancies, including infectious diseases and cancer.

abstract:
  The importance of regulatory T cells (Tregs) in balancing the effector arm of the immune system is well documented, playing a central role in preventing autoimmunity, facilitating graft tolerance following organ transplantation, and having a detrimental impact on the development of anti-tumor immunity. These regulatory responses use a variety of mechanisms to mediate suppression, including soluble factors. While IL-10 and TGF-β are the most commonly studied immunosuppressive cytokines, the recently identified IL-35 has been shown to have potent suppressive function in vitro and in vivo. Furthermore, not only does IL-35 have the ability to directly suppress effector T cell responses, it is also able to expand regulatory responses by propagating infectious tolerance and generating a potent population of IL-35-expressing inducible Tregs. In this review, we summarize research characterizing the structure and function of IL-35, examine its role in disease, and discuss how it can contribute to the induction of a distinct population of inducible Tregs.


id: cord-253862-jl1zhg13
title: SARS-CoV-2: Pathogenesis, and Advancements in Diagnostics and Treatment
author: Khalaf, Khalil
date: 2020-10-06
url: https://doi.org/10.3389/fimmu.2020.570927
doi: 10.3389/fimmu.2020.570927
abstract:
  The emergence and rapid spread of SARS-CoV-2 in December 2019 has brought the world to a standstill. While less pathogenic than the 2002–2003 SARS-CoV, this novel betacoronavirus presents a global threat due to its high transmission rate, ability to invade multiple tissues, and ability to trigger immunological hyperactivation. The identification of the animal reservoir and intermediate host were important steps toward slowing the spread of disease, and its genetic similarity to SARS-CoV has helped to determine pathogenesis and direct treatment strategies. The exponential increase in cases has necessitated fast and reliable testing procedures. Although RT-PCR remains the gold standard, it is a time-consuming procedure, paving the way for newer techniques such as serologic tests and enzyme immunoassays. Various clinical trials using broad antiviral agents in addition to novel medications have produced controversial results; however, the advancement of immunotherapy, particularly monoclonal antibodies and immune modulators is showing great promise in clinical trials. Non-orthodox medications such as anti-malarials have been tested in multiple institutions but definitive conclusions are yet to be made. Adjuvant therapies have also proven to be effective in decreasing mortality in the disease course. While no formal guidelines have been established, the multitude of ongoing clinical trials as a result of unprecedented access to research data brings us closer to halting the SARS-CoV-2 pandemic.


id: cord-254192-86ksgl5t
author: Li, Liang
date: 2019-10-17
txt: ./txt/cord-254192-86ksgl5t.txt
cache: ./cache/cord-254192-86ksgl5t.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2019.02394
doi: 10.3389/fimmu.2019.02394
summary:
  Here, to resolve the mechanism responsible for the disparity between IFN-λ3 and type I IFN in anti-mucosal virus infection, we compared the transcription profiles induced by the two IFNs in porcine intestinal epithelial (IPEC-J2) cells by RNA-Seq. Our results showed that the pretreatment of IPEC-J2 cells with IFN-λ3 resulted in the differential expression of 983 genes. Here, to resolve the mechanism responsible for the disparity between IFN-λ3 and type I IFN in anti-mucosal virus infection, we compared the transcription profiles induced by the two IFNs in porcine intestinal epithelial (IPEC-J2) cells by RNA-Seq. Our results showed that the pretreatment of IPEC-J2 cells with IFN-λ3 resulted in the differential expression of 983 genes. In this study, we comprehensively compared the transcriptional profiling of IFN-λ3-and IFN-α-induced genes in a porcine intestinal epithelial cell line (IPEC-J2) and verified the RNA-Seq results by reverse transcriptase quantitative PCR (RT-qPCR) in vitro, and further confirmed the transcriptional profile difference in crypt-derived porcine enteroids.

title:
  IFN-Lambda 3 Mediates Antiviral Protection Against Porcine Epidemic Diarrhea Virus by Inducing a Distinct Antiviral Transcript Profile in Porcine Intestinal Epithelia

abstract:
  Type III interferon-lambda (IFN-λ) plays a critical role against infection, particularly in mucosal infection in the respiratory and gastrointestinal tract. Our study and other previous studies have shown that porcine IFN-λ more efficiently curtails the infection of porcine epidemic diarrhea virus (PEDV) in the intestine epithelia than type I IFN, whereas IFN-λ3 exerts a more potent effect than IFN-λ1. However, the underlying mechanism remains elusive, and in particular, the transcriptional profile induced by IFN-λ3 has not been reported. Here, to resolve the mechanism responsible for the disparity between IFN-λ3 and type I IFN in anti-mucosal virus infection, we compared the transcription profiles induced by the two IFNs in porcine intestinal epithelial (IPEC-J2) cells by RNA-Seq. Our results showed that the pretreatment of IPEC-J2 cells with IFN-λ3 resulted in the differential expression of 983 genes. In contrast, IFN-α only modified the expression of 134 genes, and 110 of these genes were also observed in the response to IFN-λ3. A transcriptional enrichment analysis indicated that IFN-λ3 or IFN-α regulates multiple cellular processes and that IFN-λ3 activates more robust signaling pathways, particularly the antiviral Jak-STAT signaling pathway, than IFN-α. Furthermore, we verified the RNA-Seq results through an RT-qPCR analysis of IPEC-J2 cells and porcine enteroids. Moreover, transient expression of the porcine rsad2 and mx2 genes among the top 10 genes induced by IFN-λ3 significantly inhibited PEDV infection. Collectively, the data showed that IFN-λ3 induces a unique transcriptional profile that does not completely overlap with that induced by IFN-α and strongly elicits a set of genes responsible for the antiviral activity of IFN-λ3. These findings provide important knowledge regarding the elicited ISGs of type I and III IFNs in restricting porcine intestinal viral infection.


id: cord-254809-o454k6ae
title: The Metabolic Changes and Immune Profiles in Patients With COVID-19
author: He, Bing
date: 2020-08-28
txt: ./txt/cord-254809-o454k6ae.txt
cache: ./cache/cord-254809-o454k6ae.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.02075
doi: 10.3389/fimmu.2020.02075
summary:
  Third, according to an analysis of nearly 45,000 confirmed cases, 19% of patients with COVID-19 have been identified as severe cases and critically ill cases, involving severe pneumonia and metabolic disorders, developing into acute respiratory distress syndrome (ARDS), multiple organ dysfunctions (MODS), and even septic shock and death (9, 12) . In this study, we investigated mild cases and severe cases infected with SARS-CoV-2, as well as healthy young children and adults. Our study suggests that monocytes, neutrophils, and T-lymphocytes are associated with the onset and progress of COVID-19 infection, and immunopathogenesis was involved in ARDS, metabolic disorders, and MODS in severe cases. We collected the data of patients with COVID-19, including the clinical records, laboratory results and chest computed tomography (CT) scan images of mild and severe cases in the hospital. Extremely high levels of circulating lymphocytes and monocytes would benefit to fight against SARS-CoV-2 infection, which might be associated with the low morbidity of COVID-19 in young children.

abstract:
  To explore the metabolic changes and immune profiles in patients with COVID-19, we analyzed the data of patients with mild and severe COVID-19 as well as young children with COVID-19. Of the leukocytes, 47% (IQR, 33–59) were lymphocytes [2.5 × 10(9)/L (IQR, 2.2–3.3)], and monocytes were 0.51 × 10(9)/L (IQR, 0.45–0.57) in young children with COVID-19. In 32 mild COVID-19 patients, circulating monocytes were 0.45 × 10(9)/L (IQR, 0.36–0.64). Twenty-one severe patients had low PO(2) [57 mmHg (IQR, 50–73)] and SO(2) [90% (IQR, 86–93)] and high lactate dehydrogenase [580 U/L (IQR, 447–696)], cardiac troponin I [0.07 ng/mL (IQR, 0.02–0.30)], and pro-BNP [498 pg/mL (IQR, 241–1,726)]. Serum D-dimer and FDP were 9.89 mg/L (IQR, 3.62–22.85) and 32.7 mg/L (IQR, 12.8–81.9), and a large number of RBC (46/μL (IQR, 4–242) was presented in urine, a cue of disseminated intravascular coagulation (DIC) in severe patients. Three patients had comorbidity with diabetes, and 18 patients without diabetes also presented high blood glucose [7.4 mmol/L (IQR, 5.9–10.1)]. Fifteen of 21 (71%) severe cases had urine glucose +, and nine of 21 (43%) had urine ketone body +. The increased glucose was partially caused by reduced glucose consumption of cells. Severe cases had extraordinarily low serum uric acid [176 μmol/L (IQR, 131–256)]. In the late stage of COVID-19, severe cases had extremely low CD4(+) T cells and CD8(+) T cells, but unusually high neutrophils [6.5 × 10(9)/L (IQR, 4.8–9.6)], procalcitonin [0.27 ng/mL (IQR, 0.14–1.94)], C-reactive protein [66 mg/L (IQR, 25–114)] and an extremely high level of interleukin-6. Four of 21 (19%) severe cases had co-infection with fungi, and two of 21 (9%) severe cases had bacterial infection. Our findings suggest that, severe cases had acute respiratory distress syndrome (ARDS) I–III, and metabolic disorders of glucose, lipid, uric acid, etc., even multiple organ dysfunction (MODS) and DIC. Increased neutrophils and severe inflammatory responses were involved in ARDS, MODS, and DIC. With the dramatical decrease of T-lymphocytes, severe cases were susceptible to co-infect with bacteria and fungi in the late stage of COVID-19. In young children, extremely high lymphocytes and monocytes might be associated with the low morbidity of COVID-19. The significantly increased monocytes might play an important role in the recovery of patients with mild COVID-19.


id: cord-255034-x100xo2t
title: Airway Natural Killer Cells and Bacteria in Health and Disease
author: Theresine, Maud
date: 2020-09-25
url: https://doi.org/10.3389/fimmu.2020.585048
doi: 10.3389/fimmu.2020.585048
abstract:
  Natural killer (NK) cells are innate lymphoid cells at the interface between innate and adaptive immunity and mostly studied for their important roles in viral infections and malignant tumors. They can kill diseased cells and produce cytokines and chemokines, thereby shaping the adaptive immune response. Nowadays, NK cells are considered as a strong weapon for cancer immunotherapy and can for example be transduced to express tumor-specific chimeric antigen receptors or harnessed with therapeutic antibodies such as the so-called NK engagers. Whereas a large body of literature exists about the antiviral and antitumoral properties of NK cells, their potential role in bacterial infections is not that well delineated. Furthermore, NK cells are much more heterogeneous than previously thought and have tissue-characteristic features and phenotypes. This review gives an overview of airway NK cells and their position within the immunological army dressed against bacterial infections in the upper and predominantly the lower respiratory tracts. Whereas it appears that in several infections, NK cells play a non-redundant and protective role, they can likewise act as rather detrimental. The use of mouse models and the difficulty of access to human airway tissues for ethical reasons might partly explain the divergent results. However, new methods are appearing that are likely to reduce the heterogeneity between studies and to give a more coherent picture in this field.


id: cord-255578-0ltb9dpa
author: Li, Xiangru
date: 2020-06-19
txt: ./txt/cord-255578-0ltb9dpa.txt
cache: ./cache/cord-255578-0ltb9dpa.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32636836/
doi: 10.3389/fimmu.2020.01123
summary:
  title: Deficiency of Mouse FHR-1 Homolog, FHR-E, Accelerates Sepsis, and Acute Kidney Injury Through Enhancing the LPS-Induced Alternative Complement Pathway Deficiency of factor H-related protein 1 (FHR-1), which is a regulator of AP, has been considered as a susceptible factor for atypical hemolytic uremic syndrome (aHUS) and other types of nephropathy when an inducer such as infection exists. We found that murine FHR-1 homolog (FHR-E) deficiency enhanced lipopolysaccharide (LPS)-induced AP activation both in vitro and in vivo and that Cfhr1 knockout mice exhibited more severe sepsis and AKI in response to LPS challenge. These results indicated that FHR-E deficiency promoted LPS-induced sepsis and AKI through AP over-activation, providing a mouse model for studying AP regulation and sepsis. In this study, Cfhr1 was deleted on C57BL/6 mouse to study the function of FHR-E on AP and the effect of FHR-E deficiency on LPS-induced sepsis.

title:
  Deficiency of Mouse FHR-1 Homolog, FHR-E, Accelerates Sepsis, and Acute Kidney Injury Through Enhancing the LPS-Induced Alternative Complement Pathway

abstract:
  Alternative complement pathway (AP) plays an important role in the development of sepsis, which is life threatening. Deficiency of factor H-related protein 1 (FHR-1), which is a regulator of AP, has been considered as a susceptible factor for atypical hemolytic uremic syndrome (aHUS) and other types of nephropathy when an inducer such as infection exists. However, the underlying mechanism of the disease development is largely unknown. There is no report on CFHR1 gene knockout in any animal infection model and its function in vivo is still unclear. Here, a Cfhr1 knockout mouse was generated for investigating AP in sepsis and sepsis-induced acute kidney injury (AKI). We found that murine FHR-1 homolog (FHR-E) deficiency enhanced lipopolysaccharide (LPS)-induced AP activation both in vitro and in vivo and that Cfhr1 knockout mice exhibited more severe sepsis and AKI in response to LPS challenge. These results indicated that FHR-E deficiency promoted LPS-induced sepsis and AKI through AP over-activation, providing a mouse model for studying AP regulation and sepsis. This study revealed the function of FHR-E in vivo, which may further provide hints to the pathogenesis of FHR-1 deficiency-related diseases by enhancing LPS-induced AP activation.


id: cord-256582-x2grfhov
title: CLEC2 and CLEC5A: Pathogenic Host Factors in Acute Viral Infections
author: Sung, Pei-Shan
date: 2019-12-06
txt: ./txt/cord-256582-x2grfhov.txt
cache: ./cache/cord-256582-x2grfhov.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/31867016/
doi: 10.3389/fimmu.2019.02867
summary:
  Moreover, activation of CLEC2 by dengue virus (DV) and H5N1 influenza virus (IAV) induces the release of extracellular vesicles (EVs), which further enhance NETosis and proinflammatory cytokine production via CLEC5A and Toll-like receptor 2 (TLR2). Among these Sykcoupled C-type lectins, activation of CLEC5A by flaviviruses and influenza virus induces the production of inflammatory cytokines and NETosis, while these viruses also activate CLEC2 in platelets to elease extracellular vesicles (EVs), which further enhance inflammatory cytokine release and NETosis via CLEC5A and TLR2 in macrophages and neutrophils. Thus, blockade of CLEC5A-mediated signaling in DV infected cells provides a promising strategy for attenuating systemic vascular leakage and increasing the survival rate of patients suffering from DHF/DSS; this approach might also be applicable to other virus-induced inflammatory diseases (1). These viruses are captured by high affinity receptors (DC-SIGN and MR) to induce inflammatory cytokine release via activation of CLEC5A and CLEC2. Extracellular vesicles from CLEC2-activated platelets enhance dengue virus-induced lethality via CLEC5A/TLR2

abstract:
  The protective roles of endosomal toll-like receptors (TLRs) and cytosolic nucleic acid sensors are well elucidated, but the pathogenic host factors during viral infections remain unclear. Spleen tyrosine kinase (Syk)-coupled C-type lectins (CLECs) CLEC2 and CLEC5A are highly expressed on platelets and myeloid cells, respectively. CLEC2 has been shown to recognize snake venom aggretin and the endogenous ligand podoplanin and acts as a critical regulator in the development and immunothrombosis. Although CLEC2 has been reported to interact with type I immunodeficiency virus (HIV-1), its role in viral infections is still unclear. CLEC5A binds to fucose and mannose moieties of dengue virus membrane glycans, as well as to N-acetylglucosamine (GlcNAc)/N-acetylmuramic acid (MurNAc) disaccharides that form the backbone of L. monocytogenes peptidoglycans. Recently, we demonstrated that both CLEC2 and CLEC5A are critical in microbe-induced “neutrophil extracellular trap” (NET) formation and proinflammatory cytokine production. Moreover, activation of CLEC2 by dengue virus (DV) and H5N1 influenza virus (IAV) induces the release of extracellular vesicles (EVs), which further enhance NETosis and proinflammatory cytokine production via CLEC5A and Toll-like receptor 2 (TLR2). These findings not only illustrate the immunomodulatory effects of EVs during platelet-leukocyte interactions, but also demonstrate the critical roles of CLEC2 and CLEC5A in acute viral infections.


id: cord-256998-or73in8m
title: Localized Interleukin-12 for Cancer Immunotherapy
author: Nguyen, Khue G.
date: 2020-10-15
txt: ./txt/cord-256998-or73in8m.txt
cache: ./cache/cord-256998-or73in8m.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33178203/
doi: 10.3389/fimmu.2020.575597
summary:
  Among the more notable responses in other early preclinical studies, nearly half of mice bearing established B16F10 melanomas experienced complete tumor regression following 2 weekly treatments with pIL-12+EP (124) . In preclinical studies, a single intratumoral injection of mRNA encoding murine IL-12 (mIL-12) increased IFNγ expression and genes associated with a Th1 response in MC38 tumor-bearing mice (190) . In a useful comparison against other cytokines, one study demonstrated that Ad-IFN-γ had no greater antitumor activity than an empty Ad vector, whereas AdmIL-12 induced complete regressions of P815 mastocytomas in >80% of treated mice (219) . Antitumor activity on xenografts of human lung tissues indicated that liposomal encapsulation is a promising approach capable of eliminating tumor cells and inducing lymphocyte infiltration 2 weeks after i.t. injection. Immunotherapy of established tumors in mice by intratumoral injection of an adenovirus vector harboring the human IL-2 cDNA: induction of CD8 + T-cell immunity and NK activity

abstract:
  Interleukin-12 (IL-12) is a potent, pro-inflammatory type 1 cytokine that has long been studied as a potential immunotherapy for cancer. Unfortunately, IL-12's remarkable antitumor efficacy in preclinical models has yet to be replicated in humans. Early clinical trials in the mid-1990's showed that systemic delivery of IL-12 incurred dose-limiting toxicities. Nevertheless, IL-12's pleiotropic activity, i.e., its ability to engage multiple effector mechanisms and reverse tumor-induced immunosuppression, continues to entice cancer researchers. The development of strategies which maximize IL-12 delivery to the tumor microenvironment while minimizing systemic exposure are of increasing interest. Diverse IL-12 delivery systems, from immunocytokine fusions to polymeric nanoparticles, have demonstrated robust antitumor immunity with reduced adverse events in preclinical studies. Several localized IL-12 delivery approaches have recently reached the clinical stage with several more at the precipice of translation. Taken together, localized delivery systems are supporting an IL-12 renaissance which may finally allow this potent cytokine to fulfill its considerable clinical potential. This review begins with a brief historical account of cytokine monotherapies and describes how IL-12 went from promising new cure to ostracized black sheep following multiple on-study deaths. The bulk of this comprehensive review focuses on developments in diverse localized delivery strategies for IL-12-based cancer immunotherapies. Advantages and limitations of different delivery technologies are highlighted. Finally, perspectives on how IL-12-based immunotherapies may be utilized for widespread clinical application in the very near future are offered.


id: cord-257116-6td3efjw
author: Zhou, Yanrong
date: 2017-08-09
txt: ./txt/cord-257116-6td3efjw.txt
cache: ./cache/cord-257116-6td3efjw.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2017.00940
doi: 10.3389/fimmu.2017.00940
summary:
  title: Cellular RNA Helicase DDX1 Is Involved in Transmissible Gastroenteritis Virus nsp14-Induced Interferon-Beta Production In summary, our data revealed a potential coactivator role of host RNA helicase DDX1 to the induction of IFN-β response initiated by TGEV and demonstrated that nsp14 is an important IFN inducer among the TGEV-encoded proteins. In this study, we found that TGEV infection significantly facilitated IFN-β production as well as activation of the transcription factors IFN regulatory factor 3 (IRF3) and nuclear factor-kappaB (NF-κB) in porcine kidney (PK-15) cells. In summary, our data revealed a potential coactivator role of host RNA helicase DDX1 to the induction of IFN-β response initiated by TGEV and demonstrated that nsp14 is an important IFN inducer among the TGEVencoded proteins. Nsp14 interacts with cellular DExD/H helicase DDX1 to activate IFN-β in a NF-κB dependent manner, and DDX1 is associated with TGEV-induced IFN-β production, revealing a potential coactivator role of host RNA helicase DDX1 on virus and viral protein induced innate immune responses.

title:
  Cellular RNA Helicase DDX1 Is Involved in Transmissible Gastroenteritis Virus nsp14-Induced Interferon-Beta Production

abstract:
  Transmissible gastroenteritis virus (TGEV), an enteropathogenic coronavirus (CoV) of porcine, causes lethal watery diarrhea and severe dehydration in piglets and leads to severe economic losses in the swine industry. Unlike most CoVs that antagonize type I interferon (IFN) production, previous studies showed that TGEV infection induces IFN-I production both in vivo and in vitro. However, the underlying mechanism(s) remain largely unknown. In this study, we found that TGEV infection significantly facilitated IFN-β production as well as activation of the transcription factors IFN regulatory factor 3 (IRF3) and nuclear factor-kappaB (NF-κB) in porcine kidney (PK-15) cells. Screening of TGEV-encoded proteins demonstrated that non-structural protein 14 (nsp14) was the most potent IFN-β inducer and induced IFN-β production mainly by activating NF-κB but not IRF3. Further analysis showed that nsp14 interacted with DDX1, a member of the DExD/H helicase family. Knockdown of DDX1 by specific small interfering RNA (siRNA) significantly decreased nsp14-induced IFN-β production and NF-κB activation. Furthermore, TGEV-induced IFN-β production and IFN-stimulated gene (ISG) expression were decreased in cells transfected with DDX1-specific siRNA, indicating the vital role of DDX1 to TGEV-induced IFN-β responses. In summary, our data revealed a potential coactivator role of host RNA helicase DDX1 to the induction of IFN-β response initiated by TGEV and demonstrated that nsp14 is an important IFN inducer among the TGEV-encoded proteins.


id: cord-257662-viy65y72
author: Burrack, Kristina S.
date: 2014-09-08
txt: ./txt/cord-257662-viy65y72.txt
cache: ./cache/cord-257662-viy65y72.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/25250029/
doi: 10.3389/fimmu.2014.00428
summary:
  Myeloid cells, including monocytes and macrophages, play an important role in this balance, particularly through the activities of the arginine-hydrolyzing enzymes nitric oxide synthase 2 (Nos2; iNOS) and arginase 1 (Arg1). In this review, we highlight recent studies of viral infections where myeloid cell polarization -resulting in expression of iNOS or Arg1 -contribute to viral control or the development of chronic virus infection and mediate the resolution of tissue damage or cause immunopathology. It was further shown that genetic deletion of myeloid cell Arg1 resulted in enhanced viral control in inflamed muscle tissue and reduced tissue pathology following RRV infection in mice (69) , suggesting an important role for Arg1-expressing macrophages in the persistence of these chronic viruses. In the absence of iNKT cells, influenza A (PR/8 strain) infection was shown to induce the expansion of CD11b + GR-1 + MDSCs in the lungs of mice, which suppressed influenza-specific T cell and antibody responses through the activity of both arginase and NOS, resulting in higher viral titers and increased mortality (81) .

title:
  The Role of Myeloid Cell Activation and Arginine Metabolism in the Pathogenesis of Virus-Induced Diseases

abstract:
  When an antiviral immune response is generated, a balance must be reached between two opposing pathways: the production of proinflammatory and cytotoxic effectors that drive a robust antiviral immune response to control the infection and regulators that function to limit or blunt an excessive immune response to minimize immune-mediated pathology and repair tissue damage. Myeloid cells, including monocytes and macrophages, play an important role in this balance, particularly through the activities of the arginine-hydrolyzing enzymes nitric oxide synthase 2 (Nos2; iNOS) and arginase 1 (Arg1). Nitric oxide (NO) production by iNOS is an important proinflammatory mediator, whereas Arg1-expressing macrophages contribute to the resolution of inflammation and wound repair. In the context of viral infections, expression of these enzymes can result in a variety of outcomes for the host. NO has direct antiviral properties against some viruses, whereas during other virus infections NO can mediate immunopathology and/or inhibit the antiviral immune response to promote chronic infection. Arg1 activity not only has important wound healing functions but can also inhibit the antiviral immune response during some viral infections. Thus, depending on the specific virus and the tissue(s) involved, the activity of both of these arginine-hydrolyzing enzymes can either exacerbate or limit the severity of virus-induced disease. In this review, we will discuss a variety of viral infections, including HIV, SARS-CoV, LCMV, HCV, RSV, and others, where myeloid cells influence the control and clearance of the virus from the host, as well as the severity and resolution of tissue damage, via the activities of iNOS and/or Arg1. Clearly, monocyte/macrophage activation and arginine metabolism will continue to be important areas of investigation in the context of viral infections.


id: cord-259131-36udb7uc
author: Hunegnaw, Ruth
date: 2019-07-03
txt: ./txt/cord-259131-36udb7uc.txt
cache: ./cache/cord-259131-36udb7uc.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2019.01537
doi: 10.3389/fimmu.2019.01537
summary:
  AM expression of proinflammatory cytokines TNF-α, IL-6, IL-1β, and chemokine RANTES drastically increased 2-wpi compared to AMs of naïve macaques (p < 0.0001 for all), but dropped significantly with progression to chronic infection. AM expression of proinflammatory cytokines TNF-α, IL-6, IL-1β, and chemokine RANTES drastically increased 2-wpi compared to AMs of naïve macaques (p < 0.0001 for all), but dropped significantly with progression to chronic infection. In addition, the low proinflammatory cytokine response in chronic infection was not associated with an increase in IL-10-expressing AMs. To investigate AM activation, BAL cells obtained from naïve and acute and chronically infected macaques at weeks 2, 4, 8, 12, and 20 wpi, were incubated with native gp120 from R5 tropic SIV or LPS for 6 h, and intracellular expression of MIP-1β and IL-6 was assessed (Figures 3A,B) . Decreased Fc receptor expression on innate immune cells is associated with impaired antibody-mediated cellular phagocytic activity in chronically HIV-1 infected individuals

title:
  Alveolar Macrophage Dysfunction and Increased PD-1 Expression During Chronic SIV Infection of Rhesus Macaques

abstract:
  HIV infected individuals have been shown to be pre-disposed to pulmonary infections even while receiving anti-retroviral therapy. Alveolar macrophages (AMs) play a critical role in lung innate immunity, but contradictory results have been reported regarding their functionality following HIV infection. Here, using the SIV rhesus macaque model, we document the effect of SIV infection on the phenotypic and functional properties of AMs. Following infection with SIV(mac251), AMs in bronchoalveolar lavage (BAL) sampled over 2- to 20-weeks post-infection (wpi) were compared to those in BAL samples from naïve macaques. AM expression of proinflammatory cytokines TNF-α, IL-6, IL-1β, and chemokine RANTES drastically increased 2-wpi compared to AMs of naïve macaques (p < 0.0001 for all), but dropped significantly with progression to chronic infection. Phagocytic activity of AMs 2-and 4-wpi was elevated compared to AMs of naive animals (p = 0.0005, p = 0.0004, respectively) but significantly decreased by 12-wpi (p = 0.0022, p = 0.0019, respectively). By 20-wpi the ability of AMs from chronically infected animals to perform SIV-specific antibody-dependent phagocytosis (ADP) was also diminished (p = 0.028). Acute SIV infection was associated with increased FcγRIII expression which subsequently declined with disease progression. Frequency of FcγRIII(+) AMs showed a strong trend toward correlation with SIV-specific ADP, and at 2-wpi FcγRIII expression negatively correlated with viral load (r = −0.6819; p = 0.0013), suggesting a contribution to viremia control. Importantly, PD-1 was found to be expressed on AMs and showed a strong trend toward correlation with plasma viral load (r = 0.8266; p = 0.058), indicating that similar to over-expression on T-cells, PD-1 expression on AMs may also be associated with disease progression. Further, AMs predominantly expressed PD-L2, which remained consistent over the course of infection. PD-1 blockade enhanced SIV-specific ADP by AMs from chronic infection indicating that the PD-1/PD-L2 pathway may modulate functional activity of AMs at that stage. These findings provide new insight into the dynamics of SIV infection leading to AM dysfunction and alteration of pulmonary innate immunity. Our results suggest new pathways to exploit in developing therapies targeting pulmonary disease susceptibility in HIV-infected individuals.


id: cord-259748-x7dq1sy4
title: Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response
author: Wan, Dongshan
date: 2020-04-28
url: https://www.ncbi.nlm.nih.gov/pubmed/32411126/
doi: 10.3389/fimmu.2020.00615
abstract:
  Double-stranded DNA (dsDNA) sensor cyclic-GMP-AMP synthase (cGAS) along with the downstream stimulator of interferon genes (STING) acting as essential immune-surveillance mediators have become hot topics of research. The intrinsic function of the cGAS-STING pathway facilitates type-I interferon (IFN) inflammatory signaling responses and other cellular processes such as autophagy, cell survival, senescence. cGAS-STING pathway interplays with other innate immune pathways, by which it participates in regulating infection, inflammatory disease, and cancer. The therapeutic approaches targeting this pathway show promise for future translation into clinical applications. Here, we present a review of the important previous works and recent advances regarding the cGAS-STING pathway, and provide a comprehensive understanding of the modulatory pattern of the cGAS-STING pathway under multifarious pathologic states.


id: cord-260452-js4nr4d8
author: Yu, Junyang
date: 2017-10-31
txt: ./txt/cord-260452-js4nr4d8.txt
cache: ./cache/cord-260452-js4nr4d8.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2017.01420
doi: 10.3389/fimmu.2017.01420
summary:
  Both the pathogen-associated molecule pattern derived from virions and intracellular stress molecules involved in the process of viral infection lead to activation of the NLRP3 inflammasome, which in turn triggers inflammatory responses for antiviral defense and tissue healing. IL-1β and IL-18 serve to activate myriad downstream cell responses, and orchestrate innate and adaptive immunity through MyD88/IRAK4/TRAF6-mediated NF-κB signaling and the JNK/p38 mitogen-activated protein kinase pathways (60-63), which may represent key events for the NLRP3 inflammasome-dependent antiviral defense. In BV-2 mouse microglia cells infected by Japanese encephalitis virus, the NLRP3 inflammasome induces production of IL-1β and IL-18 rapidly (within 3 h of exposure) and of TNF-α, CCL2, and IL-6 later (within 6 h after exposure) (40) ; the findings suggest that the NLRP3dependent protective inflammatory response is a very early phase innate immune response against RNA viral infection.

title:
  Activation and Role of NACHT, LRR, and PYD Domains-Containing Protein 3 Inflammasome in RNA Viral Infection

abstract:
  NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation and effects during ribonucleic acid (RNA) viral infection are the focus of a wide range of research currently. Both the pathogen-associated molecule pattern derived from virions and intracellular stress molecules involved in the process of viral infection lead to activation of the NLRP3 inflammasome, which in turn triggers inflammatory responses for antiviral defense and tissue healing. However, aberrant activation of the NLRP3 inflammasome can instead support viral pathogenesis and promote disease progression. Here, we summarize and expound upon the recent literature describing the molecular mechanisms underlying the activation and effects of the NLRP3 inflammasome in RNA viral infection to highlight how it provides protection against RNA viral infection.


id: cord-261367-i1n8x0uc
author: Hwang, Ji Young
date: 2020-09-25
txt: ./txt/cord-261367-i1n8x0uc.txt
cache: ./cache/cord-261367-i1n8x0uc.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33101290/
doi: 10.3389/fimmu.2020.570661
summary:
  Instead, mice with iBALT had reduced Th2-associated mRNA expression, less eosinophil recruitment to the lungs and airways, attenuated goblet cell hyperplasia and reduced mucus production following pulmonary sensitization and challenge with OVA. To test the effect of iBALT on the immune response to a pulmonary allergen, we administered LPS (or PBS) to neonatal mice as described above, allowed the mice to rest until they were 7 weeks old, then intranasally sensitized the iBALT and control groups with 100 µg OVA in combination with low dose (0.1 µg) LPS on days 49, 50, and 51 and challenged them on days 63, 64, 67, and 68 with 25 µg OVA ( Figure 1E ). Together, these data suggest that the spatial distribution of effector Th2 cells and Tregs is affected by the presence of iBALT (they cluster together), which may explain how iBALT and control mice can have similar numbers of Th2 cells in their lungs, but have so profoundly different outcomes in terms of eosinophil accumulation and histopathology.

title:
  Inducible Bronchus–Associated Lymphoid Tissue (iBALT) Attenuates Pulmonary Pathology in a Mouse Model of Allergic Airway Disease

abstract:
  Inducible Bronchus Associated Lymphoid Tissue (iBALT) is an ectopic lymphoid tissue associated with severe forms of chronic lung diseases, including chronic obstructive pulmonary disease, rheumatoid lung disease, hypersensitivity pneumonitis and asthma, suggesting that iBALT may exacerbate these clinical conditions. However, despite the link between pulmonary pathology and iBALT formation, the role of iBALT in pathogenesis remains unknown. Here we tested whether the presence of iBALT in the lung prior to sensitization and challenge with a pulmonary allergen altered the biological outcome of disease. We found that the presence of iBALT did not exacerbate Th2 responses to pulmonary sensitization with ovalbumin. Instead, we found that mice with iBALT exhibited delayed Th2 accumulation in the lung, reduced eosinophil recruitment, reduced goblet cell hyperplasia and reduced mucus production. The presence of iBALT did not alter Th2 priming, but instead delayed the accumulation of Th2 cells in the lung following challenge and altered the spatial distribution of T cells in the lung. These results suggest that the formation of iBALT and sequestration of effector T cells in the context of chronic pulmonary inflammation may be a mechanism by which the immune system attenuates pulmonary inflammation and prevents excessive pathology.


id: cord-262375-1ex2ow07
author: Qun, Sen
date: 2020-09-02
txt: ./txt/cord-262375-1ex2ow07.txt
cache: ./cache/cord-262375-1ex2ow07.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.02160
doi: 10.3389/fimmu.2020.02160
summary:
  All confirmed patients were clinically classified according to the "Novel Coronavirus Pneumonia Treatment Scheme of the National Health Commission of the People''s Republic of China (version 7)" at the time of admission (4), as follows: (1) general type: symptoms such as fever and respiratory tract complaints were present, and manifestations of pneumonia could be seen on imaging; (2) serious type: any of the following criteria were met: (1) respiratory distress, respiratory rate (RR) ≥ 30 times/min; (2) resting oxygen saturation ≤ 93%; or (3) arterial partial oxygen pressure (PaO 2 )/oxygen absorption concentration (FiO 2 ) ≤ 300 mmHg (1 mmHg = 0.133 kPa); (3) critical type: any of the following criteria were met: (1) respiratory failure and a need for mechanical ventilation, (2) shock, or (3) a combination of factors with other organ failure requiring ICU care.

title:
  Neutrophil-to-Lymphocyte Ratios Are Closely Associated With the Severity and Course of Non-mild COVID-19

abstract:
  BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is spreading worldwide. Measuring the prevention and control of the disease has become a matter requiring urgent focus. OBJECTIVE: Based on coronavirus disease 2019 (COVID-19) clinical data from Wuhan, we conducted an in-depth analysis to clarify some of the pathological mechanisms of the disease and identify simple measures to predict its severity early on. METHODS: A total of 230 patients with non-mild COVID-19 were recruited, and information on their clinical characteristics, inflammatory cytokines, and T lymphocyte subsets was collected. Risk factors for severity were analyzed by binary logistic regression, and the associations of neutrophil-to-lymphocyte ratios (N/LRs) with illness severity, disease course, CT grading, inflammatory cytokines, and T lymphocyte subsets were evaluated. RESULTS: Our results showed that the N/LRs were closely related to interleukin (IL)-6 and IL-10 (P < 0.001, P = 0.024) and to CD3(+) and CD8(+) T lymphocytes (P < 0.001, P = 0.046). In particular, the N/LRs were positively correlated with the severity and course of the disease (P = 0.021, P < 0.001). Compared to the values at the first test after admission, IL-6 and IL-10 were significantly decreased and increased, respectively, as of the last test before discharge (P = 0.006, P < 0.001). More importantly, through binary logistic regression, we found that male sex, underlying diseases (such as cardiovascular disease), pulse, and N/LRs were all closely related to the severity of the disease (P = 0.004, P = 0.012, P = 0.013, P = 0.028). CONCLUSIONS: As a quick and convenient marker of inflammation, N/LRs may predict the disease course and severity level of non-mild COVID-19; male sex, cardiovascular disease, and pulse are also risk factors for the severity of non-mild COVID-19.


id: cord-262575-06i2nv0t
author: Caracciolo, Massimo
date: 2020-08-25
txt: ./txt/cord-262575-06i2nv0t.txt
cache: ./cache/cord-262575-06i2nv0t.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.01942
doi: 10.3389/fimmu.2020.01942
summary:
  title: Case Report: Canakinumab for the Treatment of a Patient With COVID-19 Acute Respiratory Distress Syndrome Severe cases of COVID-19 present with serious lung inflammation, acute respiratory distress syndrome and multiorgan damage. SARS-CoV-2 infection is associated with high cytokine levels, including interleukin-6 and certain subsets of immune cells, in particular, NK, distinguished according to the cell surface density of CD56. Cytokine levels are inversely correlated with lymphocyte count, therefore cytokine release syndrome may be an impediment to the adaptive immune response against SARS-CoV-2 infection. An 85 year old male presenting in our hospital with COVID-19, whose condition was complicated by acute respiratory distress syndrome and cardiac and renal failure (with oliguria) after 25 days of hospitalization, was intubated and received canakinumab for compassionate use. The immune response, including the release of pro-inflammatory cytokines and activation of T cells, are essential for controlling the viral spread, inflammation, and tissue renewal (5, 6) .

title:
  Case Report: Canakinumab for the Treatment of a Patient With COVID-19 Acute Respiratory Distress Syndrome

abstract:
  Severe cases of COVID-19 present with serious lung inflammation, acute respiratory distress syndrome and multiorgan damage. SARS-CoV-2 infection is associated with high cytokine levels, including interleukin-6 and certain subsets of immune cells, in particular, NK, distinguished according to the cell surface density of CD56. Cytokine levels are inversely correlated with lymphocyte count, therefore cytokine release syndrome may be an impediment to the adaptive immune response against SARS-CoV-2 infection. Canakinumab, a monoclonal antibody targeting IL-1β is under investigation for the treatment of severe SAR-CoV-2 infection. An 85 year old male presenting in our hospital with COVID-19, whose condition was complicated by acute respiratory distress syndrome and cardiac and renal failure (with oliguria) after 25 days of hospitalization, was intubated and received canakinumab for compassionate use. On the next day, diuresis recovered and conditions improved: high IL-6 levels and NK cells expressing CD56(bright) (associated with cytokine relase) were significantly reduced giving rise to NK CD56(dim). Patient died on day 58 with pulmonary bacterial superinfection and persistent SARS-CoV-2 positivity. In conclusion, canakinumab rescued a high risk, very elderly patient, from multiorgan damage complicating COVID-19. It may represent an useful treatment in severe cases.


id: cord-262673-j2ot35lt
author: Ahmed-Hassan, Hanaa
date: 2020-08-18
url: https://doi.org/10.3389/fimmu.2020.01979
doi: 10.3389/fimmu.2020.01979
title:
  Innate Immune Responses to Highly Pathogenic Coronaviruses and Other Significant Respiratory Viral Infections

abstract:
  The new pandemic virus SARS-CoV-2 emerged in China and spread around the world in <3 months, infecting millions of people, and causing countries to shut down public life and businesses. Nearly all nations were unprepared for this pandemic with healthcare systems stretched to their limits due to the lack of an effective vaccine and treatment. Infection with SARS-CoV-2 can lead to Coronavirus disease 2019 (COVID-19). COVID-19 is respiratory disease that can result in a cytokine storm with stark differences in morbidity and mortality between younger and older patient populations. Details regarding mechanisms of viral entry via the respiratory system and immune system correlates of protection or pathogenesis have not been fully elucidated. Here, we provide an overview of the innate immune responses in the lung to the coronaviruses MERS-CoV, SARS-CoV, and SARS-CoV-2. This review provides insight into key innate immune mechanisms that will aid in the development of therapeutics and preventive vaccines for SARS-CoV-2 infection.


id: cord-262944-9k64f0tw
title: Viral-Immune Cell Interactions at the Maternal-Fetal Interface in Human Pregnancy
author: Parker, Elaine L.
date: 2020-10-07
txt: ./txt/cord-262944-9k64f0tw.txt
cache: ./cache/cord-262944-9k64f0tw.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33117336/
doi: 10.3389/fimmu.2020.522047
summary:
  In this review, we describe mechanisms of pathogenicity of two such viral pathogens, Human cytomegalovirus (HCMV) and Zika virus (ZIKV) at the maternal-fetal interface. We will focus on the viruses human Cytomegalovirus (HCMV) and ZIKV, which are known causes of adverse pregnancy outcomes and delve into how they interact with various decidual immune cells to promote their survival and replication. We will explore further the role that NK cells play in specific viral infections in pregnancy TORCH PATHOGENS HCMV Human cytomegalovirus (HCMV) was first described in 1954 by Margaret Smith, who replicated a virus from two newborn babies who had died from cytomegalic inclusion disease (CID) (41) . A study performed using decidual and chorionic villous tissue from early and mid-gestation human pregnancy shows that ZIKV appears to elevate type I and III IFN expression, which does not occur in HCMV infection (131) .

abstract:
  The human decidua and placenta form a distinct environment distinguished for its promotion of immunotolerance to infiltrating semiallogeneic trophoblast cells to enable successful pregnancy. The maternal-fetal interface also successfully precludes transmission of most pathogens. This barrier function occurs in conjunction with a diverse influx of decidual immune cells including natural killer cells, macrophages and T cells. However, several viruses, among other microorganisms, manage to escape destruction by the host adaptive and innate immune system, leading to congenital infection and adverse pregnancy outcomes. In this review, we describe mechanisms of pathogenicity of two such viral pathogens, Human cytomegalovirus (HCMV) and Zika virus (ZIKV) at the maternal-fetal interface. Host decidual immune cell responses to these specific pathogens will be considered, along with their interactions with other cell types and the ways in which these immune cells may both facilitate and limit infection at different stages of pregnancy. Neither HCMV nor ZIKV naturally infect commonly used animal models [e.g., mice] which makes it challenging to understand disease pathogenesis. Here, we will highlight new approaches using placenta-on-a-chip and organoids models that are providing functional and physiologically relevant ways to study viral-host interaction at the maternal-fetal interface.


id: cord-263141-n200x6z1
author: Zelaya, Hortensia
date: 2016-12-23
txt: ./txt/cord-263141-n200x6z1.txt
cache: ./cache/cord-263141-n200x6z1.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/28066442/
doi: 10.3389/fimmu.2016.00633
summary:
  Studies have clearly demonstrated that hostile inflammation is accompanied by dysfunctional coagulation in respiratory IFV disease, and our investigations have proved that some immunobiotic strains are able to reduce viral disease severity through their capacity to modulate the immune-coagulative responses in the respiratory tract. Studies have clearly demonstrated that hostile inflammation is accompanied by dysfunctional coagulation in respiratory IFV disease, and our investigations have proved that some immunobiotic strains are able to reduce viral disease severity through their capacity to modulate the immune-coagulative responses in the respiratory tract. Studies have clearly demonstrated that hostile inflammation is accompanied by dysfunctional coagulation in respiratory IFV disease, and our investigations have proved that some immunobiotic strains are able to reduce viral disease severity through their capacity to modulate the immune-coagulative responses in the respiratory tract. Then, our studies were the first in demonstrating a beneficial modulation of the immune-coagulative response during respiratory TRL3 activation and IFV infection induced by immunobiotic microorganisms (Figure 3) .

title:
  Respiratory Antiviral Immunity and Immunobiotics: Beneficial Effects on Inflammation-Coagulation Interaction during Influenza Virus Infection

abstract:
  Influenza virus (IFV) is a major respiratory pathogen of global importance, and the cause of a high degree of morbidity and mortality, especially in high-risk populations such as infants, elderly, and immunocompromised hosts. Given its high capacity to change antigenically, acquired immunity is often not effective to limit IFV infection and therefore vaccination must be constantly redesigned to achieve effective protection. Improvement of respiratory and systemic innate immune mechanisms has been proposed to reduce the incidence and severity of IFV disease. In the last decade, several research works have demonstrated that microbes with the capacity to modulate the mucosal immune system (immunobiotics) are a potential alternative to beneficially modulate the outcome of IFV infection. This review provides an update of the current status on the modulation of respiratory immunity by orally and nasally administered immunobiotics, and their beneficial impact on IFV clearance and inflammatory-mediated lung tissue damage. In particular, we describe the research of our group that investigated the influence of immunobiotics on inflammation–coagulation interactions during IFV infection. Studies have clearly demonstrated that hostile inflammation is accompanied by dysfunctional coagulation in respiratory IFV disease, and our investigations have proved that some immunobiotic strains are able to reduce viral disease severity through their capacity to modulate the immune-coagulative responses in the respiratory tract.


id: cord-263433-oldy0gta
author: Barriocanal, Marina
date: 2015-01-09
txt: ./txt/cord-263433-oldy0gta.txt
cache: ./cache/cord-263433-oldy0gta.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/25620967/
doi: 10.3389/fimmu.2014.00655
summary:
  As the ISGs described to date are coding genes, we sought to determine whether IFN also regulates the expression of long non-coding ISGs. To this aim, we used RNA sequencing to analyze the transcriptome of control and HuH7 cells treated with IFNα2. To address the issue of whether IFN could also regulate expression of lncRNAs, which may play key roles in the antiviral response, we analyzed the transcriptome of cells treated or not with IFNα2 by RNA sequencing (RNASeq). The results showed that at later times post-infection with the influenza virus lacking NS1, there was increased expression of lncISG15, lncBST2/BISPR, and their neighboring coding transcripts (Figure 3A) . To discriminate whether lncISG15 and lncBST2/BISPR are induced directly by the JAK/STAT signaling pathway or by a secondary wave of the IFN response, we evaluated the expression of these lncRNAs and their coding neighboring genes in HuH7 or A549 cells incubated or not with the JAK/STAT inhibitor ruxolitinib.

title:
  Long Non-Coding RNA BST2/BISPR is Induced by IFN and Regulates the Expression of the Antiviral Factor Tetherin

abstract:
  Many long non-coding RNAs (lncRNAs) are expressed in cells but only a few have been well characterized. In these cases, lncRNAs have been shown to be key regulators of several cellular processes. Therefore, there is a great need to understand the function of more lncRNAs and their regulation in response to stimuli. Interferon (IFN) is a key molecule in the cellular antiviral response. IFN binding to its receptor activates transcription of several IFN-stimulated genes (ISGs) that function as potent antivirals. In addition, several ISGs are positive or negative regulators of the IFN pathway. This is essential to ensure a strong antiviral response and a later return of the cell to homeostasis. As the ISGs described to date are coding genes, we sought to determine whether IFN also regulates the expression of long non-coding ISGs. To this aim, we used RNA sequencing to analyze the transcriptome of control and HuH7 cells treated with IFNα2. The results show that IFN-treatment regulates the expression of several unknown non-coding transcripts. We have validated two lncRNAs upregulated after treatment with different doses of type I IFNα2 in different cells or with type III IFNλ. These lncRNAs were also induced by influenza and vesicular stomatitis virus mutants unable to block the IFN response, but not by several wild-type lytic viruses tested. These lncRNA genes were named lncISG15 and lncBST2 as they are located close to ISGs ISG15 and BST2, respectively. Interestingly, inhibition experiments showed that lncBST2 is a positive regulator of BST2. Therefore lncBST2 has been renamed BISPR, from BST2 IFN-stimulated positive regulator. Our results may have therapeutic implications as lncBST2/BISPR, but also lncISG15 and their coding neighbors, are increased in cells infected with hepatitis C virus and in the liver of infected patients. These results allow us to hypothesize that several lncRNAs could be activated by IFN to control the potency of the antiviral IFN response.


id: cord-264814-v4wnmg03
title: Progress and Pitfalls in the Quest for Effective SARS-CoV-2 (COVID-19) Vaccines
author: Flanagan, Katie L.
date: 2020-10-02
txt: ./txt/cord-264814-v4wnmg03.txt
cache: ./cache/cord-264814-v4wnmg03.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.579250
doi: 10.3389/fimmu.2020.579250
summary:
  Herein, we review the current knowledge about the immune response to this novel virus as it pertains to the design of effective and safe SARS-CoV-2 vaccines and the range of novel and established approaches to vaccine development being taken. Herein, we review the current knowledge about the immune response to this novel virus as it pertains to the design of effective and safe SARS-CoV-2 vaccines and the range of novel and established approaches to vaccine development being taken. Comprehensive safety studies are particularly critical because some candidate vaccines use platform technologies that have not been examined extensively in human subjects to date, including some of the viral vectors, mRNA and nanoparticle constructs, and because of the potential for enhanced disease and adverse events related to aberrant immune responses to be seen upon infection pre-and post-licensure.

abstract:
  There are currently around 200 SARS-CoV-2 candidate vaccines in preclinical and clinical trials throughout the world. The various candidates employ a range of vaccine strategies including some novel approaches. Currently, the goal is to prove that they are safe and immunogenic in humans (phase 1/2 studies) with several now advancing into phase 2 and 3 trials to demonstrate efficacy and gather comprehensive data on safety. It is highly likely that many vaccines will be shown to stimulate antibody and T cell responses in healthy individuals and have an acceptable safety profile, but the key will be to confirm that they protect against COVID-19. There is much hope that SARS-CoV-2 vaccines will be rolled out to the entire world to contain the pandemic and avert its most damaging impacts. However, in all likelihood this will initially require a targeted approach toward key vulnerable groups. Collaborative efforts are underway to ensure manufacturing can occur at the unprecedented scale and speed required to immunize billions of people. Ensuring deployment also occurs equitably across the globe will be critical. Careful evaluation and ongoing surveillance for safety will be required to address theoretical concerns regarding immune enhancement seen in previous contexts. Herein, we review the current knowledge about the immune response to this novel virus as it pertains to the design of effective and safe SARS-CoV-2 vaccines and the range of novel and established approaches to vaccine development being taken. We provide details of some of the frontrunner vaccines and discuss potential issues including adverse effects, scale-up and delivery.


id: cord-265005-e6rpryrh
author: Tomasello, Elena
date: 2014-10-30
url: https://www.ncbi.nlm.nih.gov/pubmed/25400632/
doi: 10.3389/fimmu.2014.00526
title:
  Harnessing Mechanistic Knowledge on Beneficial Versus Deleterious IFN-I Effects to Design Innovative Immunotherapies Targeting Cytokine Activity to Specific Cell Types

abstract:
  Type I interferons (IFN-I) were identified over 50 years ago as cytokines critical for host defense against viral infections. IFN-I promote anti-viral defense through two main mechanisms. First, IFN-I directly reinforce or induce de novo in potentially all cells the expression of effector molecules of intrinsic anti-viral immunity. Second, IFN-I orchestrate innate and adaptive anti-viral immunity. However, IFN-I responses can be deleterious for the host in a number of circumstances, including secondary bacterial or fungal infections, several autoimmune diseases, and, paradoxically, certain chronic viral infections. We will review the proposed nature of protective versus deleterious IFN-I responses in selected diseases. Emphasis will be put on the potentially deleterious functions of IFN-I in human immunodeficiency virus type 1 (HIV-1) infection, and on the respective roles of IFN-I and IFN-III in promoting resolution of hepatitis C virus (HCV) infection. We will then discuss how the balance between beneficial versus deleterious IFN-I responses is modulated by several key parameters including (i) the subtypes and dose of IFN-I produced, (ii) the cell types affected by IFN-I, and (iii) the source and timing of IFN-I production. Finally, we will speculate how integration of this knowledge combined with advanced biochemical manipulation of the activity of the cytokines should allow designing innovative immunotherapeutic treatments in patients. Specifically, we will discuss how induction or blockade of specific IFN-I responses in targeted cell types could promote the beneficial functions of IFN-I and/or dampen their deleterious effects, in a manner adapted to each disease.


id: cord-265855-zf52vl11
author: Mayor-Ibarguren, Ander
date: 2020-07-10
txt: ./txt/cord-265855-zf52vl11.txt
cache: ./cache/cord-265855-zf52vl11.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32754165/
doi: 10.3389/fimmu.2020.01736
abstract: nan
summary:
  Zinc deficiency may increase ACE-2 receptor activity on type 2 pneumocytes and other cells that are infected by SARS-COV-2, mainly in the lower respiratory tract. Although there are no specific data regarding zinc in this pathway for SARS-CoV-2, zinc may limit infection through upregulation of IFN-alpha production and an increase in its antiviral activity (77, 78) . Thus, patients with IL-6-174 GG polymorphism (C-carriers) may be susceptible to developing a severe infection due to SARS-CoV-2, leading to an increase in IL-6 levels that produce a cytokine storm related to impaired zinc homeostasis. We believe there is enough evidence to further investigate how zinc status or homeostasis is involved in the pathogenesis of severe illness produced by SARS-CoV-2 infection, and its potential role as an active treatment should be assessed in clinical trials.

title:
  A Hypothesis for the Possible Role of Zinc in the Immunological Pathways Related to COVID-19 Infection


id: cord-266085-914y3je0
title: Evaluation of Antigen-Conjugated Fluorescent Beads to Identify Antigen-Specific B Cells
author: Correa, Isabel
date: 2018-03-23
txt: ./txt/cord-266085-914y3je0.txt
cache: ./cache/cord-266085-914y3je0.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/29628923/
doi: 10.3389/fimmu.2018.00493
summary:
  To establish this, we selected Folate Receptor alpha (FRα) as a model antigen and a mouse B cell line, expressing both the soluble and the membrane-bound forms of a human/mouse chimeric antibody (MOv18 IgG1) specific for FRα, as test antibody-expressing cells. In our study, we present an antigen-conjugated fluorescent bead methodology designed to identify and isolate single antibody-expressing cells and to derive and clone matched heavy and light chain antibody variable regions into full length antibodies. The workflow features bead-based identification and isolation of specific B cells using direct fluorescent-activated cell sorting, sequencing, and cloning of matched heavy and light chain variable regions in a single full sequence antibody expression vector system, and expression and testing the antigenic reactivity of the antibody clone. Following flow sorting of single cells directly into lysis buffer, we confirmed that it is possible to extract matched H and L chain variable region sequences from single antibody-expressing cells selected by specific antigen-coated beads.

abstract:
  Selection of single antigen-specific B cells to identify their expressed antibodies is of considerable interest for evaluating human immune responses. Here, we present a method to identify single antibody-expressing cells using antigen-conjugated fluorescent beads. To establish this, we selected Folate Receptor alpha (FRα) as a model antigen and a mouse B cell line, expressing both the soluble and the membrane-bound forms of a human/mouse chimeric antibody (MOv18 IgG1) specific for FRα, as test antibody-expressing cells. Beads were conjugated to FRα using streptavidin/avidin-biotin bridges and used to select single cells expressing the membrane-bound form of anti-FRα. Bead-bound cells were single cell-sorted and processed for single cell RNA retrotranscription and PCR to isolate antibody heavy and light chain variable regions. Variable regions were then cloned and expressed as human IgG1/k antibodies. Like the original clone, engineered antibodies from single cells recognized native FRα. To evaluate whether antigen-coated beads could identify specific antibody-expressing cells in mixed immune cell populations, human peripheral blood mononuclear cells (PBMCs) were spiked with test antibody-expressing cells. Antigen-specific cells could comprise up to 75% of cells selected with antigen-conjugated beads when the frequency of the antigen-positive cells was 1:100 or higher. In PBMC pools, beads conjugated to recombinant antigens FRα and HER2 bound antigen-specific anti-FRα MOv18 and anti-HER2 Trastuzumab antibody-expressing cells, respectively. From melanoma patient-derived B cells selected with melanoma cell line-derived protein-coated fluorescent beads, we generated a monoclonal antibody that recognized melanoma antigen-coated beads. This approach may be further developed to facilitate analysis of B cells and their antibody profiles at the single cell level and to help unravel humoral immune repertoires.


id: cord-267134-5gz2dotn
author: Sallenave, Jean-Michel
date: 2020-05-28
txt: ./txt/cord-267134-5gz2dotn.txt
cache: ./cache/cord-267134-5gz2dotn.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32574272/
doi: 10.3389/fimmu.2020.01229
summary:
  The first anatomical/histological reports from the lungs of severely SARS-CoV-2-affected patients experiencing acute respiratory disease syndrome (ARDS) revealed excessive inflammatory activation and destruction of the bronchial and alveolar epithelium, features already observed during the first SARS pandemics in 2003 (3, 4). The following sections will give an overview of the molecular and cellular mechanisms underpinning SARS-CoV virus infections and how lung and systemic host innate immune responses affect survival either positively, through downregulating the initial viral load, or negatively, by triggering uncontrolled inflammation. Regarding the lung, the differentiated Calu-3 cell line [when cultured at the air-liquid interface (ALI)] is the model of choice: in that set-up, SARS-CoV infection triggered an inflammatory response characterized by increased production of interleukin (IL)-6, IL-8, gamma interferon (IFN-γ), inducible protein 10 (IP-10), and activation of the transcription factor NF-κB (56) . Innate immune response of human alveolar type II cells infected with severe acute respiratory syndrome-coronavirus

title:
  Innate Immune Signaling and Proteolytic Pathways in the Resolution or Exacerbation of SARS-CoV-2 in Covid-19: Key Therapeutic Targets?

abstract:
  COVID-19 is caused by the Severe Acute Respiratory Syndrome (SARS) coronavirus (Cov)-2, an enveloped virus with a positive-polarity, single-stranded RNA genome. The initial outbreak of the pandemic began in December 2019, and it is affecting the human health of the global community. In common with previous pandemics (Influenza H1N1 and SARS-CoV) and the epidemics of Middle east respiratory syndrome (MERS)-CoV, CoVs target bronchial and alveolar epithelial cells. Virus protein ligands (e.g., haemagglutinin or trimeric spike glycoprotein for Influenza and CoV, respectively) interact with cellular receptors, such as (depending on the virus) either sialic acids, Dipeptidyl peptidase 4 (DPP4), or angiotensin-converting enzyme 2 (ACE2). Host proteases, e.g., cathepsins, furin, or members of the type II transmembrane serine proteases (TTSP) family, such as Transmembrane protease serine 2 (TMPRSS2), are involved in virus entry by proteolytically activating virus ligands. Also involved are Toll Like Receptor (TLR) family members, which upregulate anti-viral and pro-inflammatory mediators [interleukin (IL)-6 and IL-8 and type I and type III Interferons among others], through the activation of Nuclear Factor (NF)-kB. When these events (virus cellular entry and innate immune responses) are uncontrolled, a deleterious systemic response is sometimes encountered in infected patients, leading to the well-described “cytokine storm” and an ensuing multiple organ failure promoted by a downregulation of dendritic cell, macrophage, and T-cell function. We aim to describe how the lung and systemic host innate immune responses affect survival either positively, through downregulating initial viral load, or negatively, by triggering uncontrolled inflammation. An emphasis will be put on host cellular signaling pathways and proteases involved with a view on tackling these therapeutically.


id: cord-267166-ecmayzr6
author: Savarin, Carine
date: 2018-06-11
url: https://www.ncbi.nlm.nih.gov/pubmed/29942315/
doi: 10.3389/fimmu.2018.01325
title:
  Distinct Gene Profiles of Bone Marrow-Derived Macrophages and Microglia During Neurotropic Coronavirus-Induced Demyelination

abstract:
  Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and axonal loss. Demyelinating lesions are associated with infiltrating T lymphocytes, bone marrow-derived macrophages (BMDM), and activated resident microglia. Tissue damage is thought to be mediated by T cell produced cytokines and chemokines, which activate microglia and/or BMDM to both strip myelin and produce toxic factors, ultimately damaging axons and promoting disability. However, the relative contributions of BMDM and microglia to demyelinating pathology are unclear, as their identification in MS tissue is difficult due to similar morphology and indistinguishable surface markers when activated. The CD4 T cell-induced autoimmune murine model of MS, experimental autoimmune encephalitis (EAE), in which BMDM are essential for demyelination, has revealed pathogenic and repair-promoting phenotypes associated with BMDM and microglia, respectively. Using a murine model of demyelination induced by a gliatropic coronavirus, in which BMDM are redundant for demyelination, we herein characterize gene expression profiles of BMDM versus microglia associated with demyelination. While gene expression in CNS infiltrating BMDM was upregulated early following infection and subsequently sustained, microglia expressed a more dynamic gene profile with extensive mRNA upregulation coinciding with peak demyelination after viral control. This delayed microglia response comprised a highly pro-inflammatory and phagocytic profile. Furthermore, while BMDM exhibited a mixed phenotype of M1 and M2 markers, microglia repressed the vast majority of M2-markers. Overall, these data support a pro-inflammatory and pathogenic role of microglia temporally remote from viral control, whereas BMDM retained their gene expression profile independent of the changing environment. As demyelination is caused by multifactorial insults, our results highlight the plasticity of microglia in responding to distinct inflammatory settings, which may be relevant for MS pathogenesis.


id: cord-267237-wbwlfx7q
author: Gómez-Rial, Jose
date: 2020-09-23
txt: ./txt/cord-267237-wbwlfx7q.txt
cache: ./cache/cord-267237-wbwlfx7q.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33072099/
doi: 10.3389/fimmu.2020.560381
summary:
  METHODS: Fifty-nine SARS-Cov-2 positive hospitalized patients, classified according to ICU or non-ICU admission requirement, were prospectively recruited and analyzed by ELISA for levels of sCD14 and sCD163, along with other laboratory parameters, and compared to a healthy control group. CONCLUSIONS: Monocyte-macrophage activation markers are increased and correlate with other inflammatory markers in SARS-Cov-2 infection, in association to hospital admission. In this paper, we analyze serum levels of soluble monocyte activation markers in COVID-19 patients and their correlation with severity and other inflammatory markers. We found significant correlations between sCD14 and sCD163 levels and several clinical laboratory parameters in infected patients (in these analysis, adjusted significance under Bonferrori correction is 0.01), but only in the non-ICU group, possibly reflecting an interference of the use of tocilizumab or corticoids in the ICU group. Our results thus suggest that monocyte-macrophage activation can act as driver cells of the cytokine storm and immunopathology associated to severe clinical course of COVID-19 patients.

title:
  Increased Serum Levels of sCD14 and sCD163 Indicate a Preponderant Role for Monocytes in COVID-19 Immunopathology

abstract:
  BACKGROUND: Emerging evidence indicates a potential role for monocytes in COVID-19 immunopathology. We investigated two soluble markers of monocyte activation, sCD14 and sCD163, in COVID-19 patients, with the aim of characterizing their potential role in monocyte-macrophage disease immunopathology. To the best of our knowledge, this is the first study of its kind. METHODS: Fifty-nine SARS-Cov-2 positive hospitalized patients, classified according to ICU or non-ICU admission requirement, were prospectively recruited and analyzed by ELISA for levels of sCD14 and sCD163, along with other laboratory parameters, and compared to a healthy control group. RESULTS: sCD14 and sCD163 levels were significantly higher among COVID-19 patients, independently of ICU admission requirement, compared to the control group. We found a significant correlation between sCD14 levels and other inflammatory markers, particularly Interleukin-6, in the non-ICU patients group. sCD163 showed a moderate positive correlation with the time lapsed from admission to sampling, independently of severity group. Treatment with corticoids showed an interference with sCD14 levels, whereas hydroxychloroquine and tocilizumab did not. CONCLUSIONS: Monocyte-macrophage activation markers are increased and correlate with other inflammatory markers in SARS-Cov-2 infection, in association to hospital admission. These data suggest a preponderant role for monocyte-macrophage activation in the development of immunopathology of COVID-19 patients.


id: cord-267567-w39f584z
title: Perturbation of Intracellular Cholesterol and Fatty Acid Homeostasis During Flavivirus Infections
author: Pombo, Joao Palma
date: 2018-06-04
txt: ./txt/cord-267567-w39f584z.txt
cache: ./cache/cord-267567-w39f584z.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2018.01276
doi: 10.3389/fimmu.2018.01276
summary:
  Upon flavivirus infections, these are significantly altered: on the one hand, these viruses can co-opt lipid metabolic pathways to generate ATP to facilitate replication, or to synthesize membrane components to generate replication sites; on the other hand, more recent evidence suggests counter strategies employed by host cells, which actively modulate several of these networks in response to infection, enhancing interferon signaling by doing so, and thus creating an antiviral environment. In this review, we discuss recent data on mechanisms of alteration of lipid metabolic pathways during infection by flaviviruses, with a focus on cholesterol and fatty acid biosynthesis, which can be manipulated by the invading viruses to support replication, but can also be modulated by the host immune system itself, as a means to fight infection.

abstract:
  Cellular lipid homeostasis is maintained through an intricately linked array of anabolic and catabolic pathways. Upon flavivirus infections, these are significantly altered: on the one hand, these viruses can co-opt lipid metabolic pathways to generate ATP to facilitate replication, or to synthesize membrane components to generate replication sites; on the other hand, more recent evidence suggests counter strategies employed by host cells, which actively modulate several of these networks in response to infection, enhancing interferon signaling by doing so, and thus creating an antiviral environment. In this review, we discuss recent data on mechanisms of alteration of lipid metabolic pathways during infection by flaviviruses, with a focus on cholesterol and fatty acid biosynthesis, which can be manipulated by the invading viruses to support replication, but can also be modulated by the host immune system itself, as a means to fight infection.


id: cord-268438-bjs5oliw
author: Jin, Yilin
date: 2019-12-03
txt: ./txt/cord-268438-bjs5oliw.txt
cache: ./cache/cord-268438-bjs5oliw.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/31849979/
doi: 10.3389/fimmu.2019.02805
summary:
  title: Zebrafish TRIM25 Promotes Innate Immune Response to RGNNV Infection by Targeting 2CARD and RD Regions of RIG-I for K63-Linked Ubiquitination Here, we found that zebrafish TRIM25 (zbTRIM25) functioned as a positive regulator of RLR signaling pathway during red spotted grouper nervous necrosis virus (RGNNV) infection. In the present study, zebrafish TRIM25 (zbTRIM25) was involved in RGNNV infection and was identified as a positive mediator of RLR signaling pathway by binding to and ubiquitinating the caspase activation and recruitment domain (2CARD) and repressor domain (RD) regions of RIG-I, which is different with the findings in mammals. In mammals, previous reports showed that TRIM25 enhanced RLRs antiviral pathway by binding viral RNA-activated RIG-I to induce its K63-linked polyubiquitination and subsequent IFNs and ISGs production (26) . Here, we found that zbTRIM25 positively regulated RLR signaling pathway and facilitated zbRIG-I-mediated IFN 1 promoter activation, and overexpression of zbTRIM25 inhibited RGNNV infection, indicating the conservative antiviral properties of TRIM25 in fish and mammals.

title:
  Zebrafish TRIM25 Promotes Innate Immune Response to RGNNV Infection by Targeting 2CARD and RD Regions of RIG-I for K63-Linked Ubiquitination

abstract:
  RIG-I-like receptors (RLRs) play important roles in response to virus infection by regulating host innate immune signaling pathways. Meanwhile, the RLR signaling pathway is also tightly regulated by host and virus to achieve the immune homeostasis between antiviral responses and virus survival. Here, we found that zebrafish TRIM25 (zbTRIM25) functioned as a positive regulator of RLR signaling pathway during red spotted grouper nervous necrosis virus (RGNNV) infection. Post-RGNNV infection, zbTRIM25 expression was obviously inhibited and ectopic expression of zbTRIM25 led to enhanced expression of RLR signaling pathway-related genes. Overexpression and knockdown analysis revealed that zbTRIM25 promoted zebrafish RIG-I (zbRIG-I)-mediated IFN signaling and inhibited RGNNV replication. Mechanistically, zbTRIM25 bound to zbRIG-I; in particular, the SPRY domain of zbTRIM25 interacted with the tandem caspase activation and recruitment domains (2CARD) and repressor domain (RD) regions of zbRIG-I. zbTRIM25 promoted the K63 polyubiquitination of 2CARD and RD regions of zbRIG-I. Furthermore, zbTRIM25-mediated zbRIG-I activation of IFN production was enhanced by K63-linked ubiquitin, indicating that zbTRIM25-mediated zbRIG-I polyubiquitination was essential for RIG-I-triggered IFN induction. In conclusion, these findings reveal a novel mechanism that zbTRIM25 positively regulates the innate immune response by targeting and promoting the K63-linked polyubiquitination of zbRIG-I.


id: cord-268483-joiajgs4
title: Overview of Immune Response During SARS-CoV-2 Infection: Lessons From the Past
author: Shah, Vibhuti Kumar
date: 2020-08-07
txt: ./txt/cord-268483-joiajgs4.txt
cache: ./cache/cord-268483-joiajgs4.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.01949
doi: 10.3389/fimmu.2020.01949
summary:
  As there are no specific treatments available for this novel coronavirus, numerous small molecular drugs that are being used for the treatment of diseases like SARS, MERS, HIV, ebola, malaria, and tuberculosis are being given to COVID-19 patients, and clinical trials for many such drugs have already begun. An ELISA-based time kinetics study to detect the COVID-19 specific humoral immune response showed that the patients produced IgM and IgG antibodies that did not cross-react with other human coronaviruses except SARS-CoV. A case study on pediatric patients reports that 5 out of 6 children showed a protective humoral response, with neutralizing IgG and IgM antibodies targeting the N and S-RBD proteins of SARS-CoV-2 (65) . T cell responses are required for protection from clinical disease and for virus clearance in severe acute respiratory syndrome coronavirus-infected mice

abstract:
  After the 1918 flu pandemic, the world is again facing a similar situation. However, the advancement in medical science has made it possible to identify that the novel infectious agent is from the coronavirus family. Rapid genome sequencing by various groups helped in identifying the structure and function of the virus, its immunogenicity in diverse populations, and potential preventive measures. Coronavirus attacks the respiratory system, causing pneumonia and lymphopenia in infected individuals. Viral components like spike and nucleocapsid proteins trigger an immune response in the host to eliminate the virus. These viral antigens can be either recognized by the B cells or presented by MHC complexes to the T cells, resulting in antibody production, increased cytokine secretion, and cytolytic activity in the acute phase of infection. Genetic polymorphism in MHC enables it to present some of the T cell epitopes very well over the other MHC alleles. The association of MHC alleles and its downregulated expression has been correlated with disease severity against influenza and coronaviruses. Studies have reported that infected individuals can, after recovery, induce strong protective responses by generating a memory T-cell pool against SARS-CoV and MERS-CoV. These memory T cells were not persistent in the long term and, upon reactivation, caused local damage due to cross-reactivity. So far, the reports suggest that SARS-CoV-2, which is highly contagious, shows related symptoms in three different stages and develops an exhaustive T-cell pool at higher loads of viral infection. As there are no specific treatments available for this novel coronavirus, numerous small molecular drugs that are being used for the treatment of diseases like SARS, MERS, HIV, ebola, malaria, and tuberculosis are being given to COVID-19 patients, and clinical trials for many such drugs have already begun. A classical immunotherapy of convalescent plasma transfusion from recovered patients has also been initiated for the neutralization of viremia in terminally ill COVID-19 patients. Due to the limitations of plasma transfusion, researchers are now focusing on developing neutralizing antibodies against virus particles along with immuno-modulation of cytokines like IL-6, Type I interferons (IFNs), and TNF-α that could help in combating the infection. This review highlights the similarities of the coronaviruses that caused SARS and MERS to the novel SARS-CoV-2 in relation to their pathogenicity and immunogenicity and also focuses on various treatment strategies that could be employed for curing COVID-19.


id: cord-268501-z4oztgi0
title: What Would Jenner and Pasteur Have Done About COVID-19 Coronavirus? The Urges of a Vaccinologist
author: Palatnik-de-Sousa, Clarisa B.
date: 2020-08-26
txt: ./txt/cord-268501-z4oztgi0.txt
cache: ./cache/cord-268501-z4oztgi0.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32983183/
doi: 10.3389/fimmu.2020.02173
abstract: nan
summary:
  In fact, by May 11th, 2020 seven vaccines had already entered Phase I clinical trials: (1) encapsulated mRNA encoding protein S (Moderna and NIAID, USA); (2) Adenovirus expressing protein S (Cansino Biologics, China); (3) DCs modified with lentivirus expressing several proteins and CTLs (Shenzen Geno-Immune Medical, China); (4) an APC modified with lentivirus expressing several viral proteins (35); (5) Inno 4800, SARS CoV2 DNA Injection (Innovio, USA); (6) ChAdOx1 vaccine from the Jenner Institute, Oxford University, (UK) which is a genetically modified Adenovirus expressing Coronavirus proteins (39) , and is also being tested in a Phase II trial; and finally (7) the whole inactivated coronavirus with Alum by Sinovac, China (40) . Furthermore, in vaccinated monkeys, seven days after infection, the Sinovac inactivated vaccine at 6 µg/dose induced high titers of IgG antibodies directed against the S, RBD and lower levels of anti-N protein antibodies, high titers of virus neutralizing antibodies with no detected antibodydependent enhancement of disease (ADE) (40) .


id: cord-268511-dx2cqqt5
author: Kunkl, Martina
date: 2020-10-14
txt: ./txt/cord-268511-dx2cqqt5.txt
cache: ./cache/cord-268511-dx2cqqt5.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.590964
doi: 10.3389/fimmu.2020.590964
summary:
  We have previously described that human CD28, a crucial co-stimulatory receptor necessary for full T cell activation, is also able to act as a TCR independent signaling receptor and to induce the expression of IL-17A and inflammatory cytokines related to Th17 cells, which together with Th22 cells represent the main cellular source of IL-22. However, although IL-6 itself is able to prime IL-22 production in activated human CD4 + T cells (41) , stimulation of CD4 + T cells with IL-6 alone is not sufficient for up-regulating IL-22 gene expression ( Figure 1G ) but requires a second signal delivered by CD28. During CD28 stimulation, RelA/NF-kB and IL-6-associated STAT3 cooperate for inducing IL-22 expression and secretion ( Figure 3 ) that in turn acts on epithelial cells by promoting the up-regulation of MUC1 ( Figure 4) .

title:
  CD28 Autonomous Signaling Orchestrates IL-22 Expression and IL-22-Regulated Epithelial Barrier Functions in Human T Lymphocytes

abstract:
  IL-22 is a member of the IL-10 cytokine family involved in host protection against extracellular pathogens, by promoting epithelial cell regeneration and barrier functions. Dysregulation of IL-22 production has also frequently been observed in acute respiratory distress syndrome (ARDS) and several chronic inflammatory and autoimmune diseases. We have previously described that human CD28, a crucial co-stimulatory receptor necessary for full T cell activation, is also able to act as a TCR independent signaling receptor and to induce the expression of IL-17A and inflammatory cytokines related to Th17 cells, which together with Th22 cells represent the main cellular source of IL-22. Here we characterized the role of CD28 autonomous signaling in regulating IL-22 expression in human CD4(+) T cells. We show that CD28 stimulation in the absence of TCR strongly up-regulates IL-22 gene expression and secretion. As recently observed for IL-17A, we also found that CD28-mediated regulation of IL-22 transcription requires the cooperative activities of both IL-6-activated STAT3 and RelA/NF-κB transcription factors. CD28-mediated IL-22 production also promotes the barrier functions of epithelial cells by inducing mucin and metalloproteases expression. Finally, by using specific inhibitory drugs, we also identified CD28-associated class 1A phosphatidylinositol 3-kinase (PI3K) as a pivotal mediator of CD28-mediated IL-22 expression and IL-22–dependent epithelial cell barrier functions.


id: cord-268781-6l74rrlm
title: Multiplex Screening Assay for Identifying Cytotoxic CD8(+) T Cell Epitopes
author: Poh, Chek Meng
date: 2020-03-11
txt: ./txt/cord-268781-6l74rrlm.txt
cache: ./cache/cord-268781-6l74rrlm.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.00400
doi: 10.3389/fimmu.2020.00400
summary:
  Besides, our results from human PBMCs and three independent infectious animal models (MERS, influenza and malaria) further reveal that IFNγ expression by epitope-specific CD8 + T cells does not always correlate with their cell-killing potential, highlighting the need for using cytotoxicity assays in specific contexts (e.g., evaluating vaccine candidates). Besides, our results from human PBMCs and three independent infectious animal models (MERS, influenza and malaria) further reveal that IFNγ expression by epitope-specific CD8 + T cells does not always correlate with their cell-killing potential, highlighting the need for using cytotoxicity assays in specific contexts (e.g., evaluating vaccine candidates). Splenocytes from vaccinated mice challenged by a lethal PR8 infection were used to measure epitope-specific CD8 T cell effector functions through direct (in vivo cytotoxicity) and indirect (IFNγ-ICS) assays.

abstract:
  The cytotoxicity of epitope-specific CD8(+) T cells is usually measured indirectly through IFNγ production. Existing assays that directly measure this activity are limited mainly to measurements of up to two specificities in a single reaction. Here, we develop a multiplex cytotoxicity assay that allows direct, simultaneous measurement of up to 23 different specificities of CD8(+) T cells in a single reaction. This can greatly reduce the amount of starting clinical materials for a systematic screening of CD8(+) T cell epitopes. In addition, this greatly enhanced capacity enables the incorporation of irrelevant epitopes for determining the non-specific killing activity of CD8(+) T cells, thereby allowing to measure the actual epitope-specific cytotoxicity activities. This technique is shown to be useful to study both human and mouse CD8(+) T cells. Besides, our results from human PBMCs and three independent infectious animal models (MERS, influenza and malaria) further reveal that IFNγ expression by epitope-specific CD8(+) T cells does not always correlate with their cell-killing potential, highlighting the need for using cytotoxicity assays in specific contexts (e.g., evaluating vaccine candidates). Overall, our approach opens up new possibilities for comprehensive analyses of CD8(+) T cell cytotoxicity in a practical manner.


id: cord-269170-9f460xbq
title: Our Evolving Understanding of Kawasaki Disease Pathogenesis: Role of the Gut Microbiota
author: Kaneko, Kazunari
date: 2020-07-24
txt: ./txt/cord-269170-9f460xbq.txt
cache: ./cache/cord-269170-9f460xbq.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32793240/
doi: 10.3389/fimmu.2020.01616
summary:
  The disease seems to result from the interplay of genetic and environmental susceptibility factors with infectious triggers, followed by a subsequent abnormal immune response characterized by increased levels of inflammatory cytokines and chemokines during the acute phase. Recent advances in culture-independent techniques for detection and identification of intestinal commensal bacteria enabled the discovery that Th17 and Treg differentiation are regulated by short chain fatty acids (SCFAs), in particular butyrate, produced by the gut microbiota. This perspective is illustrated in Figure 1 and can be explained as follows: [1] various factors during the in utero and postnatal period drive dysbiosis in young children; [2] dysbiosis results in reduced intestinal production of SCFAs including butyrate; [3] reduced levels of SCFAs in the gut cause an imbalance of Th17s/Tregs; and [4] individuals with Th17/Treg imbalances develop hypercytokinemia triggered by ubiquitous infectious agents(s), followed by KD (Figure 1) .

abstract:
  Kawasaki disease (KD) was first described by Dr. Tomisaku Kawasaki in 1967. The etiology of KD has been studied comprehensively but remains largely unknown. The disease seems to result from the interplay of genetic and environmental susceptibility factors with infectious triggers, followed by a subsequent abnormal immune response characterized by increased levels of inflammatory cytokines and chemokines during the acute phase. Evidence has mounted to suggest that an imbalance between T helper 17 cells (Th17s) and regulatory T cells (Tregs) is associated with aberrant immune responses in KD. Recent advances in culture-independent techniques for detection and identification of intestinal commensal bacteria enabled the discovery that Th17 and Treg differentiation are regulated by short chain fatty acids (SCFAs), in particular butyrate, produced by the gut microbiota. This finding provided a mechanistic link between dysbiosis, defined as changes in the composition of the gut microbiota, and various inflammatory diseases. On this basis, we propose that dysbiosis, with reduced production of SCFAs leading to imbalances of Th17s/Tregs, could be involved in the etiology of KD. A pilot study supported this hypothesis, as only fecal concentrations of butyrate were significantly reduced in KD patients among SCFAs. This evolving perspective prompted us to undertake metagenomic analyses of bacterial DNA from the feces of KD patients who were antibiotic-naïve at diagnosis. Simultaneous measurements of Th17s/Tregs in peripheral blood and SCFA concentrations in feces would provide valuable information regarding the association between dysbiosis and dysregulated immune responses in KD.


id: cord-269222-g2ibmo75
title: Role of Lactobacilli and Lactoferrin in the Mucosal Cervicovaginal Defense
author: Valenti, Piera
date: 2018-03-01
url: https://doi.org/10.3389/fimmu.2018.00376
doi: 10.3389/fimmu.2018.00376
abstract:
  The innate defense system of the female mucosal genital tract involves a close and complex interaction among the healthy vaginal microbiota, different cells, and various proteins that protect the host from pathogens. Vaginal lactobacilli and lactoferrin represent two essential actors in the vaginal environment. Lactobacilli represent the dominant bacterial species able to prevent facultative and obligate anaerobes outnumber in vaginal microbiota maintaining healthy microbial homeostasis. Several mechanisms underlie the protection exerted by lactobacilli: competition for nutrients and tissue adherence, reduction of the vaginal pH, modulation of immunity, and production of bioactive compounds. Among bioactive factors of cervicovaginal mucosa, lactoferrin, an iron-binding cationic glycoprotein, is a multifunctional glycoprotein with antibacterial, antifungal, antiviral, and antiparasitic activities, recently emerging as an important modulator of inflammation. Lactobacilli and lactoferrin are largely under the influence of female hormones and of paracrine production of various cytokines. Lactoferrin is strongly increased in lower genital tract mucosal fluid of women affected by Neisseria gonorrheae, Chlamydia trachomatis, and Trichomonas vaginalis infections promoting both innate and adaptive immune responses. In vaginal dysbiosis characterized by low amounts of vaginal lactobacilli and increased levels of endogenous anaerobic bacteria, the increase in lactoferrin could act as an immune modulator assuming the role normally played by the healthy microbiota in vaginal mucosa. Then lactoferrin and lactobacilli may be considered as biomarkers of altered microbial homeostasis at vaginal level. Considering the shortage of effective treatments to counteract recurrent and/or antibiotic-resistant bacterial infections, the intravaginal administration of lactobacilli and lactoferrin could be a novel efficient therapeutic strategy and a valuable tool to restore mucosal immune homeostasis.


id: cord-273277-4ewvwg4o
author: Rudd, Christopher E.
date: 2020-06-26
url: https://doi.org/10.3389/fimmu.2020.01638
doi: 10.3389/fimmu.2020.01638
title:
  GSK-3 Inhibition as a Therapeutic Approach Against SARs CoV2: Dual Benefit of Inhibiting Viral Replication While Potentiating the Immune Response

abstract:
  The SARS-CoV2 (COVID-19) pandemic and uncertainties in developing a vaccine have created an urgent need for new therapeutic approaches. A key question is whether it is possible to make rational predictions of new therapies based on the presently available scientific and medical information. In this regard, I have noticed an omission in the present analysis in the literature related to the exploitation of glycogen synthase kinase 3 (GSK-3) as a therapeutic approach. This is based on two key observations, that GSK-3 inhibitors can simultaneously block SARs viral replication, while boosting CD8+ adaptive T-cell and innate natural killer (NK) responses. Firstly, it is already clear that GSK-3 phosphorylation of SARs CoV1 N protein on key serine residues is needed for viral replication such that small molecule inhibitors (SMIs) of GSK-3 can inhibit viral replication. In comparing protein sequences, I show here that the key sites in the N protein of SARs CoV1 N for replication are conserved in SARs CoV2. This strongly suggests that GSK-3 SMIs will also inhibit SARs Cov2 replication. Secondly, we and others have previously documented that GSK-3 SMIs markedly enhance CD8+ cytolytic T-cell (CTL) and NK cell anti-viral effector functions leading to a reduction in both acute and chronic viral infections in mice. My hypothesis is that the repurposing of low-cost inhibitors of GSK-3 such as lithium will limit SARS-CoV2 infections by both reducing viral replication and potentiating the immune response against the virus. To date, there has been no mention of this dual connection between GSK-3 and SARs CoV2 in the literature. To my knowledge, no other drugs exist with the potential to simultaneously target both viral replication and immune response against SARs CoV2.


id: cord-273505-pcsw3vmx
author: Liu, Xiaosheng
date: 2020-07-14
url: https://doi.org/10.3389/fimmu.2020.01660
doi: 10.3389/fimmu.2020.01660
title:
  High-Dose Intravenous Immunoglobulins in the Treatment of Severe Acute Viral Pneumonia: The Known Mechanisms and Clinical Effects

abstract:
  The current outbreak of viral pneumonia, caused by novel coronavirus SARS-CoV-2, is the focus of worldwide attention. The WHO declared the COVID-19 outbreak a pandemic event on Mar 12, 2020, and the number of confirmed cases is still on the rise worldwide. While most infected individuals only experience mild symptoms or may even be asymptomatic, some patients rapidly progress to severe acute respiratory failure with substantial mortality, making it imperative to develop an efficient treatment for severe SARS-CoV-2 pneumonia alongside supportive care. So far, the optimal treatment strategy for severe COVID-19 remains unknown. Intravenous immunoglobulin (IVIg) is a blood product pooled from healthy donors with high concentrations of immunoglobulin G (IgG) and has been used in patients with autoimmune and inflammatory diseases for more than 30 years. In this review, we aim to highlight the known mechanisms of immunomodulatory effects of high-dose IVIg therapy, the immunopathological hypothesis of viral pneumonia, and the clinical evidence of IVIg therapy in viral pneumonia. We then make cautious therapeutic inferences about high-dose IVIg therapy in treating severe COVID-19. These inferences may provide relevant and useful insights in order to aid treatment for COVID-19.


id: cord-274557-2071770h
title: On the Dark Side of Therapies with Immunoglobulin Concentrates: The Adverse Events
author: Späth, Peter J.
date: 2015-02-05
url: https://www.ncbi.nlm.nih.gov/pubmed/25699039/
doi: 10.3389/fimmu.2015.00011
abstract:
  Therapy by human immunoglobulin G (IgG) concentrates is a success story ongoing for decades with an ever increasing demand for this plasma product. The success of IgG concentrates on a clinical level is documented by the slowly increasing number of registered indication and the more rapid increase of the off-label uses, a topic dealt with in another contribution to this special issue of Frontiers in Immunology. A part of the success is the adverse event (AE) profile of IgG concentrates which is, even at life-long need for therapy, excellent. Transmission of pathogens in the last decade could be entirely controlled through the antecedent introduction by authorities of a regulatory network and installing quality standards by the plasma fractionation industry. The cornerstone of the regulatory network is current good manufacturing practice. Non-infectious AEs occur rarely and mainly are mild to moderate. However, in recent times, the increase in frequency of hemolytic and thrombotic AEs raised worrying questions on the possible background for these AEs. Below, we review elements of non-infectious AEs, and particularly focus on hemolysis and thrombosis. We discuss how the introduction of plasma fractionation by ion-exchange chromatography and polishing by immunoaffinity chromatographic steps might alter repertoire of specificities and influence AE profiles and efficacy of IgG concentrates.


id: cord-275779-ocbygkyb
author: Ye, Zi-Wei
date: 2017-03-21
url: https://doi.org/10.3389/fimmu.2017.00317
doi: 10.3389/fimmu.2017.00317
title:
  Antibody-Dependent Cell-Mediated Cytotoxicity Epitopes on the Hemagglutinin Head Region of Pandemic H1N1 Influenza Virus Play Detrimental Roles in H1N1-Infected Mice

abstract:
  Engaging the antibody-dependent cell-mediated cytotoxicity (ADCC) for killing of virus-infected cells and secretion of antiviral cytokines and chemokines was incorporated as one of the important features in the design of universal influenza vaccines. However, investigation of the ADCC epitopes on the highly immunogenic influenza hemagglutinin (HA) head region has been rarely reported. In this study, we determined the ADCC and antiviral activities of two putative ADCC epitopes, designated E1 and E2, on the HA head of a pandemic H1N1 influenza virus in vitro and in a lethal mouse model. Our data demonstrated that sera from the E1-vaccinated mice could induce high ADCC activities. Importantly, the induction of ADCC response modestly decreased viral load in the lungs of H1N1-infected mice. However, the elevated ADCC significantly increased mouse alveolar damage and mortality than that of the PBS-vaccinated group (P < 0.0001). The phenotype was potentially due to an exaggerated inflammatory cell infiltration triggered by ADCC, as an upregulated release of cytotoxic granules (perforin) was observed in the lung tissue of E1-vaccinated mice after H1N1 influenza virus challenge. Overall, our data suggested that ADCC elicited by certain domains of HA head region might have a detrimental rather than protective effect during influenza virus infection. Thus, future design of universal influenza vaccine shall strike a balance between the induction of protective immunity and potential side effects of ADCC.


id: cord-277529-z2r14w2k
title: Familial Mediterranean Fever and COVID-19: Friends or Foes?
author: Stella, Alessandro
date: 2020-09-18
url: https://doi.org/10.3389/fimmu.2020.574593
doi: 10.3389/fimmu.2020.574593
abstract:
  Familial Mediterranean Fever (FMF) and COVID-19 show a remarkable overlap of clinical symptoms and similar laboratory findings. Both are characterized by fever, abdominal/chest pain, elevation of C-reactive protein, and leukocytosis. In addition, colchicine and IL-1 inhibitors treatments that are effective in controlling inflammation in FMF patients have recently been proposed for off-label use in COVID-19 patients. Thus, FMF may resemble a milder recapitulation of the cytokine storm that is a hallmark of COVID-19 patients progressing to severe disease. We analyzed the sequence of the MEFV-encoded Pyrin protein – whose mutations cause FMF- in mammals, bats and pangolin. Intriguingly, although Pyrin is extremely conserved in species that are considered either a reservoir or intermediate hosts for SARS-CoV-2, some of the most common FMF-causing variants in humans are present as wildtype residues in these species. We propose that in humans, Pyrin may have evolved to fight highly pathogenic infections.


id: cord-278081-tk7vn1v1
title: Viral Impact in Autoimmune Diseases: Expanding the “X Chromosome–Nucleolus Nexus” Hypothesis
author: Brooks, Wesley H.
date: 2017-11-28
txt: ./txt/cord-278081-tk7vn1v1.txt
cache: ./cache/cord-278081-tk7vn1v1.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2017.01657
doi: 10.3389/fimmu.2017.01657
summary:
  Here is presented new details to the hypothesis, explaining how the disrupted chromatin can lead to subsequent disruption of the nucleolus, even nucleolar fragmentation, which results in ineffective nucleolar functioning, misfolded RNAs, misassembled or incompletely assembled ribonucleoprotein (RNP) complexes, and stabilization of nucleolar components in autoantigenic conformations. For now there is no direct connection between viruses and the "X chromosome-nucleolus nexus" hypothesis to the increased risk of cancers among autoimmune disease patients but we can consider the induction by viruses of increased polyamine levels and the possible reactivation of X-linked polyamine genes as means by which competition for the cellular methyl donor, SAM, could reduce DNA methylation and open oncogenes for overexpression in proliferation competent cells. A disrupted Barr body could generate an abundance of polyamines and Alu RNA from X-linked genes and elements that further stress and damage the nucleolus, making it very inefficient in its functions, even fragmenting it and possibly leading to cell death.

abstract:
  Viruses are suspected of significant roles in autoimmune diseases but the mechanisms are unclear. We get some insight by considering demands a virus places on host cells. Viruses not only require production of their own proteins, RNA and/or DNA, but also production of additional cellular machinery, such as ribosomes, to handle the increased demands. Since the nucleolus is a major site of RNA processing and ribonucleoprotein assembly, nucleoli are targeted by viruses, directly when viral RNA and proteins enter the nucleolus and indirectly when viruses induce increased expression of cellular polyamine genes. Polyamines are at high levels in nucleoli to assist in RNA folding. The size and activity of nucleoli increase directly with increases in polyamines. Nucleolar expansion due to abnormal increases in polyamines could disrupt nearby chromatin, such as the inactive X chromosome, leading to expression of previously sequestered DNA. Sudden expression of a large concentration of Alu elements from the disrupted inactive X can compete with RNA transcripts containing intronic Alu sequences that normally maintain nucleolar structural integrity. Such disruption of nucleolar activity can lead to misfolded RNAs, misassembled ribonucleoprotein complexes, and fragmentation of the nucleolus. Many autoantigens in lupus are, at least transiently, components of the nucleolus. Considering these effects of viruses, the “X chromosome–nucleolus nexus” hypothesis, which proposed disruption of the inactive X by the nucleolus during stress, is now expanded here to propose subsequent disruption of the nucleolus by previously sequestered Alu elements, which can fragment the nucleolus, leading to generation of autoantigens.


id: cord-278839-uu2wlpmp
title: Pregnancy, Viral Infection, and COVID-19
author: Alberca, Ricardo Wesley
date: 2020-07-07
txt: ./txt/cord-278839-uu2wlpmp.txt
cache: ./cache/cord-278839-uu2wlpmp.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32733490/
doi: 10.3389/fimmu.2020.01672
summary:
  In 2009, during the H1N1 flu pandemic, an increased ratio of female to male cases was verified, in which pregnant women developed more complications, as severe acute respiratory syndrome, and higher mortality compared to the general population (30, 31) . Additionally, infection by the Lassa virus in pregnant women shows high levels of placental replication, and the risk of maternal-fetal mortality increases with the duration of pregnancy (38, 39) . At first, contagion occurred through contact with some infected animals but, soon there were the first reports of human-to-human transmission (93), The virus was identified as belonging to the coronaviridae family and was designated SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) (94). Chen and collaborators, verified alteration in calcium and albumin levels in the blood of pregnant women with SARS-CoV-2 infection (124) , which could potentially increase the severity in COVID-19 (125) .

abstract:
  Pregnancy comprises a unique immunological condition, to allow fetal development and to protect the host from pathogenic infections. Viral infections during pregnancy can disrupt immunological tolerance and may generate deleterious effects on the fetus. Despite these possible links between pregnancy and infection-induced morbidity, it is unclear how pregnancy interferes with maternal response to some viral pathogens. In this context, the novel coronavirus (SARS-CoV-2) can induce the coronavirus diseases-2019 (COVID-19) in pregnant women. The potential risk of vertical transmission is unclear, babies born from COVID-19-positive mothers seems to have no serious clinical symptoms, the possible mechanisms are discussed, which highlights that checking the children's outcome and more research is warranted. In this review, we investigate the reports concerning viral infections and COVID-19 during pregnancy, to establish a correlation and possible implications of COVID-19 during pregnancy and neonatal's health.


id: cord-279105-e2zjxjox
title: Serological Approaches for COVID-19: Epidemiologic Perspective on Surveillance and Control
author: Lee, Cheryl Yi-Pin
date: 2020-04-24
txt: ./txt/cord-279105-e2zjxjox.txt
cache: ./cache/cord-279105-e2zjxjox.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32391022/
doi: 10.3389/fimmu.2020.00879
summary:
  With the limitations of qRT-PCR, immunoassays may offer another FIGURE 2 | Schematic illustration on the window period of detection for either viral RNA or antibodies in SARS-CoV-2-infected individuals. However, interestingly, one study demonstrated that longitudinal profiling of both antibodies in a population of 63 COVID-19 patients showed no specific chronological order in terms of IgM and IgG seroconversion (10) , which was also observed in patients infected with SARS-CoV and another human coronavirus, Middle East Respiratory Syndrome coronavirus (MERS-CoV) (22, 23) . These findings on SARS-CoV-2-specific antibodies seroconversion against the S viral protein suggest the importance to test for both IgM and IgG antibodies to confirm a positive infection. With the availability of immunoassays utilizing various coronavirus structural proteins, the use of more than one different antigen-based serological approach may be essential to establish a true positive SARS-CoV-2 infection.

abstract:
  Since December 2019, the novel coronavirus, SARS-CoV-2, has garnered global attention due to its rapid transmission, which has infected more than two million people worldwide. Early detection of SARS-CoV-2 is one of the crucial interventions to control virus spread and dissemination. Molecular assays have been the gold standard to directly detect for the presence of viral genetic material in infected individuals. However, insufficient viral RNA at the point of detection may lead to false negative results. As such, it is important to also employ immune-based assays to determine one's exposure to SARS-CoV-2, as well as to assist in the surveillance of individuals with prior exposure to SARS-CoV-2. Within a span of 4 months, extensive studies have been done to develop serological systems to characterize the antibody profiles, as well as to identify and generate potentially neutralizing antibodies during SARS-CoV-2 infection. The vast diversity of novel findings has added value to coronavirus research, and a strategic consolidation is crucial to encompass the latest advances and developments. This review aims to provide a concise yet extensive collation of current immunoassays for SARS-CoV-2, while discussing the strengths, limitations and applications of antibody detection in SARS-CoV-2 research and control.


id: cord-280605-2i4gk7et
author: Bachmann, María Consuelo
date: 2020-10-14
url: https://www.ncbi.nlm.nih.gov/pubmed/33162985/
doi: 10.3389/fimmu.2020.570083
title:
  The Challenge by Multiple Environmental and Biological Factors Induce Inflammation in Aging: Their Role in the Promotion of Chronic Disease

abstract:
  The aging process is driven by multiple mechanisms that lead to changes in energy production, oxidative stress, homeostatic dysregulation and eventually to loss of functionality and increased disease susceptibility. Most aged individuals develop chronic low-grade inflammation, which is an important risk factor for morbidity, physical and cognitive impairment, frailty, and death. At any age, chronic inflammatory diseases are major causes of morbimortality, affecting up to 5–8% of the population of industrialized countries. Several environmental factors can play an important role for modifying the inflammatory state. Genetics accounts for only a small fraction of chronic-inflammatory diseases, whereas environmental factors appear to participate, either with a causative or a promotional role in 50% to 75% of patients. Several of those changes depend on epigenetic changes that will further modify the individual response to additional stimuli. The interaction between inflammation and the environment offers important insights on aging and health. These conditions, often depending on the individual’s sex, appear to lead to decreased longevity and physical and cognitive decline. In addition to biological factors, the environment is also involved in the generation of psychological and social context leading to stress. Poor psychological environments and other sources of stress also result in increased inflammation. However, the mechanisms underlying the role of environmental and psychosocial factors and nutrition on the regulation of inflammation, and how the response elicited for those factors interact among them, are poorly understood. Whereas certain deleterious environmental factors result in the generation of oxidative stress driven by an increased production of reactive oxygen and nitrogen species, endoplasmic reticulum stress, and inflammation, other factors, including nutrition (polyunsaturated fatty acids) and behavioral factors (exercise) confer protection against inflammation, oxidative and endoplasmic reticulum stress, and thus ameliorate their deleterious effect. Here, we discuss processes and mechanisms of inflammation associated with environmental factors and behavior, their links to sex and gender, and their overall impact on aging.


id: cord-280924-g6062fwk
author: Hachim, Mahmood Yaseen
date: 2020-06-10
txt: ./txt/cord-280924-g6062fwk.txt
cache: ./cache/cord-280924-g6062fwk.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.01372
doi: 10.3389/fimmu.2020.01372
summary:
  title: Interferon-Induced Transmembrane Protein (IFITM3) Is Upregulated Explicitly in SARS-CoV-2 Infected Lung Epithelial Cells We identified IFITM3 as an early upregulated gene, and valproic acid was found to enhance its mRNA expression as well as induce its antiviral action. To effectively address the ongoing COVID-19 pandemic, there is a recognized need for a framework for rapid identification of novel targets for diagnostic and therapeutic interventions as well as determine clinically approved drugs with high potential for repurposed use against SARS-CoV-2. In this study, we have applied this approach, and our findings have identified IFITM3 as an early upregulated gene and indicate that valproic acid enhances IFITM3 mRNA expression and antiviral action. Our toxicogenomic analysis showed that valproic acid increased the mRNA expression of IFITM3, supporting a new report that the SARS-CoV-2-human protein-protein interaction map showed that valproic acid might be a potential repurposing drug for COVID-19 (34) .

title:
  Interferon-Induced Transmembrane Protein (IFITM3) Is Upregulated Explicitly in SARS-CoV-2 Infected Lung Epithelial Cells

abstract:
  Current guidelines for COVID-19 management recommend the utilization of various repurposed drugs. Despite ongoing research toward the development of a vaccine against SARS-CoV-2, such a vaccine will not be available in time to contribute to the containment of the ongoing pandemic. Therefore, there is an urgent need to develop a framework for the rapid identification of novel targets for diagnostic and therapeutic interventions. We analyzed publicly available transcriptomic datasets of SARS-CoV infected humans and mammals to identify consistent differentially expressed genes then validated in SARS-CoV-2 infected epithelial cells transcriptomic datasets. Comprehensive toxicogenomic analysis of the identified genes to identify possible interactions with clinically proven drugs was carried out. We identified IFITM3 as an early upregulated gene, and valproic acid was found to enhance its mRNA expression as well as induce its antiviral action. These findings indicate that analysis of publicly available transcriptomic and toxicogenomic data represents a rapid approach for the identification of novel targets and molecules that can modify the action of such targets during the early phases of emerging infections like COVID-19.


id: cord-280941-ds6x0yym
author: Kim, Young-Seok
date: 2018-05-17
url: https://doi.org/10.3389/fimmu.2018.01093
doi: 10.3389/fimmu.2018.01093
title:
  Chaperna-Mediated Assembly of Ferritin-Based Middle East Respiratory Syndrome-Coronavirus Nanoparticles

abstract:
  The folding of monomeric antigens and their subsequent assembly into higher ordered structures are crucial for robust and effective production of nanoparticle (NP) vaccines in a timely and reproducible manner. Despite significant advances in in silico design and structure-based assembly, most engineered NPs are refractory to soluble expression and fail to assemble as designed, presenting major challenges in the manufacturing process. The failure is due to a lack of understanding of the kinetic pathways and enabling technical platforms to ensure successful folding of the monomer antigens into regular assemblages. Capitalizing on a novel function of RNA as a molecular chaperone (chaperna: chaperone + RNA), we provide a robust protein-folding vehicle that may be implemented to NP assembly in bacterial hosts. The receptor-binding domain (RBD) of Middle East respiratory syndrome-coronavirus (MERS-CoV) was fused with the RNA-interaction domain (RID) and bacterioferritin, and expressed in Escherichia coli in a soluble form. Site-specific proteolytic removal of the RID prompted the assemblage of monomers into NPs, which was confirmed by electron microscopy and dynamic light scattering. The mutations that affected the RNA binding to RBD significantly increased the soluble aggregation into amorphous structures, reducing the overall yield of NPs of a defined size. This underscored the RNA-antigen interactions during NP assembly. The sera after mouse immunization effectively interfered with the binding of MERS-CoV RBD to the cellular receptor hDPP4. The results suggest that RNA-binding controls the overall kinetic network of the antigen folding pathway in favor of enhanced assemblage of NPs into highly regular and immunologically relevant conformations. The concentration of the ion Fe(2+), salt, and fusion linker also contributed to the assembly in vitro, and the stability of the NPs. The kinetic “pace-keeping” role of chaperna in the super molecular assembly of antigen monomers holds promise for the development and delivery of NPs and virus-like particles as recombinant vaccines and for serological detection of viral infections.


id: cord-282081-qaagup4d
title: Nanobodies—Useful Tools for Allergy Treatment?
author: Flicker, Sabine
date: 2020-09-30
url: https://doi.org/10.3389/fimmu.2020.576255
doi: 10.3389/fimmu.2020.576255
abstract:
  In the last decade single domain antibodies (nanobodies, V(H)H) qualified through their unique characteristics have emerged as accepted and even advantageous alternative to conventional antibodies and have shown great potential as diagnostic and therapeutic tools. Currently nanobodies find their main medical application area in the fields of oncology and neurodegenerative diseases. According to late-breaking information, nanobodies specific for coronavirus spikes have been generated these days to test their suitability as useful therapeutics for future outbreaks. Their superior properties such as chemical stability, high affinity to a broad spectrum of epitopes, low immunogenicity, ease of their generation, selection and production proved nanobodies also to be remarkable to investigate their efficacy for passive treatment of type I allergy, an exaggerated immune reaction to foreign antigens with increasing global prevalence.


id: cord-282336-zvc04s39
author: Choudhary, Ishita
date: 2020-09-02
txt: ./txt/cord-282336-zvc04s39.txt
cache: ./cache/cord-282336-zvc04s39.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.02164
doi: 10.3389/fimmu.2020.02164
summary:
  In contrast, the lung injury in LPS-challenged TTP KO mice was characterized by severe consolidation (>90% of total area of lung section) (Figures 1F,G) that included infiltration of neutrophils, edema, fibrin, and airspace hemorrhage within the airway and alveolar lumen, multifocal loss of bronchiolar epithelium with infiltration of neutrophils and red blood cells within the bronchiolar lumen, and moderate to severe perivascular edema and inflammation (Figures 1F-H) . To determine the cell-specific role of TTP levels in ALI, we modulated TTP levels in hematopoietic progenitor cells (HPCs) and non-HPCs. In order to test whether donor HPCs repopulate the recipient mouse lungs, we first made bone marrow chimeras in which total body irradiated WT mice were transplanted with HPCs from a mouse expressing green fluorescent protein (GFP) in their somatic cells.

title:
  Tristetraprolin Overexpression in Non-hematopoietic Cells Protects Against Acute Lung Injury in Mice

abstract:
  Tristetraprolin (TTP) is a mRNA binding protein that binds to adenylate-uridylate-rich elements within the 3′ untranslated regions of certain transcripts, such as tumor necrosis factor (Tnf) mRNA, and increases their rate of decay. Modulation of TTP expression is implicated in inflammation; however, its role in acute lung inflammation remains unknown. Accordingly, we tested the role of TTP in lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. LPS-challenged TTP-knockout (TTP(KO)) mice, as well as myeloid cell-specific TTP-deficient (TTP(myeKO)) mice, exhibited significant increases in lung injury, although these responses were more robust in the TTP(KO). Mice with systemic overexpression of TTP (TTP(ΔARE)) were protected from ALI, as indicated by significantly reduced neutrophilic infiltration, reduced levels of neutrophil chemoattractants, and histological parameters of ALI. Interestingly, while irradiated wild-type (WT) mice reconstituted with TTP(KO) hematopoietic progenitor cells (HPCs) showed exaggerated ALI, their reconstitution with the TTP(ΔARE) HPCs mitigated ALI. The reconstitution of irradiated TTP(ΔARE) mice with HPCs from either WT or TTP(ΔARE) donors conferred significant protection against ALI. In contrast, irradiated TTP(ΔARE) mice reconstituted with TTP(KO) HPCs had exaggerated ALI, but the response was milder as compared to WT recipients that received TTP(KO) HPCs. Finally, the reconstitution of irradiated TTP(KO) recipient mice with TTP(ΔARE) HPCs did not confer any protection to the TTP(KO) mice. These data together suggest that non-HPCs-specific overexpression of TTP within the lungs protects against ALI via downregulation of neutrophil chemoattractants and reduction in neutrophilic infiltration.


id: cord-283382-t890r7xp
title: Factors Which Contribute to the Immunogenicity of Non-replicating Adenoviral Vectored Vaccines
author: Coughlan, Lynda
date: 2020-05-19
url: https://doi.org/10.3389/fimmu.2020.00909
doi: 10.3389/fimmu.2020.00909
abstract:
  Adenoviral vectors are a safe and potently immunogenic vaccine delivery platform. Non-replicating Ad vectors possess several attributes which make them attractive vaccines for infectious disease, including their capacity for high titer growth, ease of manipulation, safety, and immunogenicity in clinical studies, as well as their compatibility with clinical manufacturing and thermo-stabilization procedures. In general, Ad vectors are immunogenic vaccines, which elicit robust transgene antigen-specific cellular (namely CD8(+) T cells) and/or humoral immune responses. A large number of adenoviruses isolated from humans and non-human primates, which have low seroprevalence in humans, have been vectorized and tested as vaccines in animal models and humans. However, a distinct hierarchy of immunological potency has been identified between diverse Ad vectors, which unfortunately limits the potential use of many vectors which have otherwise desirable manufacturing characteristics. The precise mechanistic factors which underlie the profound disparities in immunogenicity are not clearly defined and are the subject of ongoing, detailed investigation. It has been suggested that a combination of factors contribute to the potent immunogenicity of particular Ad vectors, including the magnitude and duration of vaccine antigen expression following immunization. Furthermore, the excessive induction of Type I interferons by some Ad vectors has been suggested to impair transgene expression levels, dampening subsequent immune responses. Therefore, the induction of balanced, but not excessive stimulation of innate signaling is optimal. Entry factor binding or receptor usage of distinct Ad vectors can also affect their in vivo tropism following administration by different routes. The abundance and accessibility of innate immune cells and/or antigen-presenting cells at the site of injection contributes to early innate immune responses to Ad vaccination, affecting the outcome of the adaptive immune response. Although a significant amount of information exists regarding the tropism determinants of the common human adenovirus type-5 vector, very little is known about the receptor usage and tropism of rare species or non-human Ad vectors. Increased understanding of how different facets of the host response to Ad vectors contribute to their immunological potency will be essential for the development of optimized and customized Ad vaccine platforms for specific diseases.


id: cord-283505-ousbar6c
title: The Dynamics of the Ferret Immune Response During H7N9 Influenza Virus Infection
author: Horman, William S. J.
date: 2020-09-24
txt: ./txt/cord-283505-ousbar6c.txt
cache: ./cache/cord-283505-ousbar6c.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33072098/
doi: 10.3389/fimmu.2020.559113
summary:
  To elucidate the cellular immune mechanisms associated with disease severity and progression, we used a ferret model to closely resemble disease outcomes in humans following influenza virus infection. In this study, we aimed to examine the ferret immune response to H7N9 influenza virus infection by analyzing leukocyte population variation associated with disease pathogenesis. While the day 6 ferret which showed worsened disease progression did exhibit the most severe lung pathology, the lack of viral antigen in and around these lesions (Supplementary Figure 1) means they cannot conclusively be classified as being caused by the influenza infection, and thus we are hesitant to classify disease presentation in this ferret as like a high pathogenicity infection based on the histopathology findings regardless of the increase in clinical signs. Highly pathogenic avian influenza virus infection in chickens but not ducks is associated with elevated host immune and pro-inflammatory responses

abstract:
  As the recent outbreak of SARS-CoV-2 has highlighted, the threat of a pandemic event from zoonotic viruses, such as the deadly influenza A/H7N9 virus subtype, continues to be a major global health concern. H7N9 virus strains appear to exhibit greater disease severity in mammalian hosts compared to natural avian hosts, though the exact mechanisms underlying this are somewhat unclear. Knowledge of the H7N9 host-pathogen interactions have mainly been constrained to natural sporadic human infections. To elucidate the cellular immune mechanisms associated with disease severity and progression, we used a ferret model to closely resemble disease outcomes in humans following influenza virus infection. Intriguingly, we observed variable disease outcomes when ferrets were inoculated with the A/Anhui/1/2013 (H7N9) strain. We observed relatively reduced antigen-presenting cell activation in lymphoid tissues which may be correlative with increased disease severity. Additionally, depletions in CD8(+) T cells were not apparent in sick animals. This study provides further insight into the ways that lymphocytes maturate and traffic in response to H7N9 infection in the ferret model.


id: cord-284156-btb4oodz
title: Host and Viral Modulation of RIG-I-Mediated Antiviral Immunity
author: Liu, Yiliu
date: 2017-01-03
txt: ./txt/cord-284156-btb4oodz.txt
cache: ./cache/cord-284156-btb4oodz.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/28096803/
doi: 10.3389/fimmu.2016.00662
summary:
  Retinoic acid-inducible gene-I (RIG-I) is critical in triggering antiviral and inflammatory responses for the control of viral replication in response to cytoplasmic virus-specific RNA structures. They function as cytoplasmic sensors for the recognition of a variety of RNA viruses and subsequent activation of downstream signaling to drive type I IFN production and antiviral gene expressions. (c) Interactions between RIG-I-TRIM25 complex and 14-3-3ϵ promote RIG-I translocation to mitochondrial mitochondrial antiviral signaling protein (MAVS) for downstream signaling, leading to interferon production. Protein purification and mass spectrometry analysis identified that phosphorylation of Thr170 in the CARDs antagonizes RIG-I signaling by inhibiting TRIM25-mediated Lys172 ubiquitination and MAVS binding (68) . Ebola virus VP35 protein binds double-stranded RNA and inhibits alpha/beta interferon production induced by RIG-I signaling Inhibition of dengue and chikungunya virus infections by RIG-I-mediated type I interferon-independent stimulation of the innate antiviral response

abstract:
  Innate immunity is the first line of defense against invading pathogens. Rapid and efficient detection of pathogen-associated molecular patterns via pattern-recognition receptors is essential for the host to mount defensive and protective responses. Retinoic acid-inducible gene-I (RIG-I) is critical in triggering antiviral and inflammatory responses for the control of viral replication in response to cytoplasmic virus-specific RNA structures. Upon viral RNA recognition, RIG-I recruits the mitochondrial adaptor protein mitochondrial antiviral signaling protein, which leads to a signaling cascade that coordinates the induction of type I interferons (IFNs), as well as a large variety of antiviral interferon-stimulated genes. The RIG-I activation is tightly regulated via various posttranslational modifications for the prevention of aberrant innate immune signaling. By contrast, viruses have evolved mechanisms of evasion, such as sequestrating viral structures from RIG-I detections and targeting receptor or signaling molecules for degradation. These virus–host interactions have broadened our understanding of viral pathogenesis and provided insights into the function of the RIG-I pathway. In this review, we summarize the recent advances regarding RIG-I pathogen recognition and signaling transduction, cell-intrinsic control of RIG-I activation, and the viral antagonism of RIG-I signaling.


id: cord-284409-xiyeceib
author: Prabakaran, Ponraj
date: 2014-08-28
url: https://doi.org/10.3389/fimmu.2014.00398
doi: 10.3389/fimmu.2014.00398
title:
  The Antibody Germline/Maturation Hypothesis, Elicitation of Broadly Neutralizing Antibodies Against HIV-1 and Cord Blood IgM Repertoires

abstract:
  We have previously observed that all known potent broadly neutralizing antibodies (bnAbs) against HIV-1 are highly divergent from their putative germline predecessors in contrast to bnAbs against viruses causing acute infections such as henipaviruses and SARS CoV, which are much less divergent from their germline counterparts. Consequently, we have hypothesized that germline antibodies may not bind to the HIV-1 envelope glycoprotein (Env) because they are so different compared to the highly somatically mutated HIV-1-specific bnAbs. We have further hypothesized that the immunogenicity of highly conserved epitopes on the HIV-1 envelope glycoproteins (Envs) may be reduced or eliminated by their very weak or absent interactions with germline antibodies and immune responses leading to the elicitation of bnAbs may not be initiated and/or sustained. Even if such responses are initiated, the maturation pathways are so extraordinarily complex that prolonged periods of time may be required for elicitation of bnAbs with defined unique sequences. We provided the initial evidence supporting this antibody germline/maturation hypothesis, which prompted a number of studies to design vaccine immunogens that could bind putative germline predecessors of known bnAbs and to explore complex B cell lineages. However, guiding the immune system through the exceptionally complex antibody maturation pathways to elicit known bnAbs remains a major challenge. Here, we discuss studies exploring the antibody germline/maturation hypothesis as related to elicitation of bnAbs against HIV-1 and present our recent data demonstrating the existence of germline-like precursors of VRC01 antibodies in a human cord blood IgM library.


id: cord-284867-p4jgyusp
author: Schöler, Lara
date: 2020-10-09
txt: ./txt/cord-284867-p4jgyusp.txt
cache: ./cache/cord-284867-p4jgyusp.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.573526
doi: 10.3389/fimmu.2020.573526
summary:
  Altogether, the SARS-CoV-2 icELISA test allows rapid (<48 h in total, read-out in seconds) and automated quantification of virus infection in cell culture to evaluate the efficacy of NAbs and antiviral drugs using reagents and equipment present in most routine diagnostics departments. The fact that the infection and the resulting icELISA signal were neutralized by NAbs present in immune sera indicated that the fast and automated icELISA format is applicable for icNTs. Although most SARS-CoV-2 NTs have not been formally validated and certified, classic plaque reduction neutralization tests (PRNT) are currently considered to represent the gold standard for the detection of SARS-CoV-2-specific NAbs. Various commercially available IgM, IgA, and IgG ELISAs have been compared to PRNTs [e.g., (30) ]. Given the excellent signal-to-noise ratio between infected and uninfected cells, the test was applicable to quantify the efficacy of antiviral compounds, here shown for IFNb, and SARS-CoV-2-specific NAbs present in immune sera.

title:
  A Novel In-Cell ELISA Assay Allows Rapid and Automated Quantification of SARS-CoV-2 to Analyze Neutralizing Antibodies and Antiviral Compounds

abstract:
  The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently the most pressing medical and socioeconomic challenge. Constituting important correlates of protection, the determination of virus-neutralizing antibodies (NAbs) is indispensable for convalescent plasma selection, vaccine candidate evaluation, and immunity certificates. In contrast to standard serological ELISAs, plaque reduction neutralization tests (PRNTs) are laborious, time-consuming, expensive, and restricted to specialized laboratories. To replace microscopic counting-based SARS-CoV-2 PRNTs by a novel assay exempt from genetically modified viruses, which are inapplicable in most diagnostics departments, we established a simple, rapid, and automated SARS-CoV-2 neutralization assay employing an in-cell ELISA (icELISA) approach. After optimization of various parameters such as virus-specific antibodies, cell lines, virus doses, and duration of infection, SARS-CoV-2-infected cells became amenable as direct antigen source for quantitative icELISA. Antiviral agents such as human sera containing NAbs or antiviral interferons dose dependently reduced the SARS-CoV-2-specific signal. Applying increased infectious doses, the icELISA-based neutralization test (icNT) was superior to PRNT in discriminating convalescent sera with high from those with intermediate neutralizing capacities. In addition, the icNT was found to be specific, discriminating between SARS-CoV-2-specific NAbs and those raised against other coronaviruses. Altogether, the SARS-CoV-2 icELISA test allows rapid (<48 h in total, read-out in seconds) and automated quantification of virus infection in cell culture to evaluate the efficacy of NAbs and antiviral drugs using reagents and equipment present in most routine diagnostics departments.


id: cord-285760-y37ji92k
author: Connell, Anna R.
date: 2020-09-18
url: https://www.ncbi.nlm.nih.gov/pubmed/33072071/
doi: 10.3389/fimmu.2020.02089
title:
  Mumps Outbreaks in Vaccinated Populations—Is It Time to Re-assess the Clinical Efficacy of Vaccines?

abstract:
  History illustrates the remarkable public health impact of mass vaccination, by dramatically improving life expectancy and reducing the burden of infectious diseases and co-morbidities worldwide. It has been perceived that if an individual adhered to the MMR vaccine schedule that immunity to mumps virus (MuV) would be lifelong. Recent mumps outbreaks in individuals who had received two doses of the Measles Mumps Rubella (MMR) vaccine has challenged the efficacy of the MMR vaccine. However, clinical symptoms, complications, viral shedding and transmission associated with mumps infection has been shown to be reduced in vaccinated individuals, demonstrating a benefit of this vaccine. Therefore, the question of what constitutes a good mumps vaccine and how its impact is assessed in this modern era remains to be addressed. Epidemiology of the individuals most affected by the outbreaks (predominantly young adults) and variance in the circulating MuV genotype have been well-described alluding to a collection of influences such as vaccine hesitancy, heterogeneous vaccine uptake, primary, and/or secondary vaccine failures. This review aims to discuss in detail the interplay of factors thought to be contributing to the current mumps outbreaks seen in highly vaccinated populations. In addition, how mumps diagnoses has progressed and impacted the understanding of mumps infection since a mumps vaccine was first developed, the limitations of current laboratory tests in confirming protection in vaccinated individuals and how vaccine effectiveness is quantified are also considered. By highlighting knowledge gaps within this area, this state-of-the-art review proposes a change of perspective regarding the impact of a vaccine in a highly vaccinated population from a clinical, diagnostic and public perspective, highlighting a need for a paradigm shift on what is considered vaccine immunity.


id: cord-286337-qk90xb3a
title: Respiratory Viral Infection-Induced Microbiome Alterations and Secondary Bacterial Pneumonia
author: Hanada, Shigeo
date: 2018-11-16
url: https://doi.org/10.3389/fimmu.2018.02640
doi: 10.3389/fimmu.2018.02640
abstract:
  Influenza and other respiratory viral infections are the most common type of acute respiratory infection. Viral infections predispose patients to secondary bacterial infections, which often have a more severe clinical course. The mechanisms underlying post-viral bacterial infections are complex, and include multifactorial processes mediated by interactions between viruses, bacteria, and the host immune system. Studies over the past 15 years have demonstrated that unique microbial communities reside on the mucosal surfaces of the gastrointestinal tract and the respiratory tract, which have both direct and indirect effects on host defense against viral infections. In addition, antiviral immune responses induced by acute respiratory infections such as influenza are associated with changes in microbial composition and function (“dysbiosis”) in the respiratory and gastrointestinal tract, which in turn may alter subsequent immune function against secondary bacterial infection or alter the dynamics of inter-microbial interactions, thereby enhancing the proliferation of potentially pathogenic bacterial species. In this review, we summarize the literature on the interactions between host microbial communities and host defense, and how influenza, and other acute respiratory viral infections disrupt these interactions, thereby contributing to the pathogenesis of secondary bacterial infections.


id: cord-288496-7rrh2gg6
title: A Systematic, Unbiased Mapping of CD8(+) and CD4(+) T Cell Epitopes in Yellow Fever Vaccinees
author: Stryhn, Anette
date: 2020-08-31
url: https://www.ncbi.nlm.nih.gov/pubmed/32983097/
doi: 10.3389/fimmu.2020.01836
abstract:
  Examining CD8(+) and CD4(+) T cell responses after primary Yellow Fever vaccination in a cohort of 210 volunteers, we have identified and tetramer-validated 92 CD8(+) and 50 CD4(+) T cell epitopes, many inducing strong and prevalent (i.e., immunodominant) T cell responses. Restricted by 40 and 14 HLA-class I and II allotypes, respectively, these responses have wide population coverage and might be of considerable academic, diagnostic and therapeutic interest. The broad coverage of epitopes and HLA overcame the otherwise confounding effects of HLA diversity and non-HLA background providing the first evidence of T cell immunodomination in humans. Also, double-staining of CD4(+) T cells with tetramers representing the same HLA-binding core, albeit with different flanking regions, demonstrated an extensive diversification of the specificities of many CD4(+) T cell responses. We suggest that this could reduce the risk of pathogen escape, and that multi-tetramer staining is required to reveal the true magnitude and diversity of CD4(+) T cell responses. Our T cell epitope discovery approach uses a combination of (1) overlapping peptides representing the entire Yellow Fever virus proteome to search for peptides containing CD4(+) and/or CD8(+) T cell epitopes, (2) predictors of peptide-HLA binding to suggest epitopes and their restricting HLA allotypes, (3) generation of peptide-HLA tetramers to identify T cell epitopes, and (4) analysis of ex vivo T cell responses to validate the same. This approach is systematic, exhaustive, and can be done in any individual of any HLA haplotype. It is all-inclusive in the sense that it includes all protein antigens and peptide epitopes, and encompasses both CD4(+) and CD8(+) T cell epitopes. It is efficient and, importantly, reduces the false discovery rate. The unbiased nature of the T cell epitope discovery approach presented here should support the refinement of future peptide-HLA class I and II predictors and tetramer technologies, which eventually should cover all HLA class I and II isotypes. We believe that future investigations of emerging pathogens (e.g., SARS-CoV-2) should include population-wide T cell epitope discovery using blood samples from patients, convalescents and/or long-term survivors, who might all hold important information on T cell epitopes and responses.


id: cord-291941-9a4tt4f7
author: Barber-Axthelm, Isaac M.
date: 2020-08-18
txt: ./txt/cord-291941-9a4tt4f7.txt
cache: ./cache/cord-291941-9a4tt4f7.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33013862/
doi: 10.3389/fimmu.2020.02038
summary:
  Herein, we discuss the current state of MAIT cell characterization in NHPs [which has focused on rhesus macaques (RM), pigtail macaques (PTM), and Mauritian cynomolgus macaques (MCM)] and the changes in MAIT cell populations that occur during simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) infection, which are the critical animal models for HIV infection. MAIT cells are consistently maintained at low frequencies in secondary lymphoid organs (lymph nodes and spleen) compared to the peripheral blood, in both humans and NHPs. This is attributed to the relative lack of CCR7 and CD62L expression, both required for lymphoid tissue homing, on peripheral MAIT cells [reviewed in Kurioka et al. The lack of MAIT cell depletion during acute infection is consistent with what has been observed in humans during initial HIV infection and emphasizes the importance of the NHP-SIV/SHIV model to study MAIT cell dynamics during peracute infection.

title:
  Understanding the Role of Mucosal-Associated Invariant T-Cells in Non-human Primate Models of HIV Infection

abstract:
  Chronic HIV infection causes systemic immune activation and dysregulation, resulting in the impairment of most T-cell subsets including MAIT cells. Multiple human cohort studies demonstrate MAIT cells are selectively depleted in the peripheral blood and lymphoid tissues during HIV infection, with incomplete restoration during suppressive antiretroviral therapy. Because MAIT cells play an important role in mucosal defense against a wide array of pathogens, fully reconstituting the MAIT cell compartment in ART-treated populations could improve immunity against co-infections. Non-human primates (NHPs) are a valuable, well-described animal model for HIV infection in humans. NHPs also maintain MAIT cell frequencies more comparable to humans, compared to other common animal models, and provide a unique opportunity to study MAIT cells in the circulation and mucosal tissues in a longitudinal manner. Only recently, however, have NHP MAIT cells been thoroughly characterized using macaque-specific MR1 tetramer reagents. Here we review the similarities and differences between MAIT cells in humans and NHPs as well as the impact of SIV/SHIV infection on MAIT cells and the potential implications for future research.


id: cord-293736-nyvwv31m
title: COVID-19: Underlying Adipokine Storm and Angiotensin 1-7 Umbrella
author: Méry, Geoffroy
date: 2020-07-21
url: https://www.ncbi.nlm.nih.gov/pubmed/32793244/
doi: 10.3389/fimmu.2020.01714
abstract:
  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third coronavirus leading to a global health outbreak. Despite the high mortality rates from SARS-CoV-1 and Middle-East respiratory syndrome (MERS)-CoV infections, which both sparked the interest of the scientific community, the underlying physiopathology of the SARS-CoV-2 infection, remains partially unclear. SARS-CoV-2 shares similar features with SARS-CoV-1, notably the use of the angiotensin conversion enzyme 2 (ACE2) as a receptor to enter the host cells. However, some features of the SARS-CoV-2 pandemic are unique. In this work, we focus on the association between obesity, metabolic syndrome, and type 2 diabetes on the one hand, and the severity of COVID-19 infection on the other, as it seems greater in these patients. We discuss how adipocyte dysfunction leads to a specific immune environment that predisposes obese patients to respiratory failure during COVID-19. We also hypothesize that an ACE2-cleaved protein, angiotensin 1-7, has a beneficial action on immune deregulation and that its low expression during the SARS-CoV-2 infection could explain the severity of infection. This introduces angiotensin 1-7 as a potential candidate of interest in therapeutic research on CoV infections.


id: cord-295302-vwrxentv
title: Potential SARS-CoV-2 Preimmune IgM Epitopes
author: Shivarov, Velizar
date: 2020-04-30
txt: ./txt/cord-295302-vwrxentv.txt
cache: ./cache/cord-295302-vwrxentv.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32425955/
doi: 10.3389/fimmu.2020.00932
summary:
  While studying the human public IgM igome as represented by a library of 224,087 linear mimotopes, three exact matches to peptides in the proteins of SARS-CoV-2 were found: two in the open reading frame 1ab and one in the spike protein. For the present study, the degrees of the vertices representing the natural SARS-CoV-2 epitopes, all of which belonged to the giant component, were used as the number of adjacent mimotopes parameter. A simple comparison for exact matches to peptides from the SARS-CoV-2 proteome yielded 3 heptapeptides-two in the open reading frame 1ab ( 3518 AQTGIAV 3524 and 5198 TKGPHEF 5204 ) and one in the spike protein ( 108 TTLDSKT 114 ). This loop is adjacent to the loop representing the epitope of the neutralizing antibody LCA60 on the SARS-CoV spike (8, 9) . Thus, it is quite possible that the SARS-CoV-2 spike epitope TTLDSKT is bound by B cells that will contribute to the induced immune response.

abstract:
  While studying the human public IgM igome as represented by a library of 224,087 linear mimotopes, three exact matches to peptides in the proteins of SARS-CoV-2 were found: two in the open reading frame 1ab and one in the spike protein. Joining the efforts to fast track SARS-CoV-2 vaccine development, here we describe briefly these potential epitopes in comparison to mimotopes representing peptides of SARS-CoV, HCoV 229E and OC43.


id: cord-295416-y3lvcjqd
author: Eichinger, Katherine M.
date: 2020-07-29
url: https://doi.org/10.3389/fimmu.2020.01673
doi: 10.3389/fimmu.2020.01673
title:
  Prefusion RSV F Immunization Elicits Th2-Mediated Lung Pathology in Mice When Formulated With a Th2 (but Not a Th1/Th2-Balanced) Adjuvant Despite Complete Viral Protection

abstract:
  Respiratory syncytial virus (RSV) remains the most common cause of lower respiratory tract infections in children worldwide. Development of a vaccine has been hindered by the risk of developing enhanced respiratory disease (ERD) upon natural exposure to the virus. Generation of higher quality neutralizing antibodies with stabilized pre-fusion F protein antigens has been proposed as a strategy to prevent ERD. We sought to test whether there was evidence of ERD in naïve BALB/c mice immunized with an unadjuvanted, stabilized pre-fusion F protein, and challenged with RSV line 19. We further sought to determine the extent to which formulation with a Th2-biased (alum) or a more Th1/Th2-balanced (Advax-SM) adjuvant influenced cellular responses and lung pathology. When exposed to RSV, mice immunized with pre-fusion F protein alone (PreF) exhibited increased airway eosinophilia and mucus accumulation. This was further exacerbated by formulation of PreF with Alum (aluminum hydroxide). Conversely, formulation of PreF with a Th1/Th2-balanced adjuvant, Advax-SM, not only suppressed RSV viral replication, but also inhibited airway eosinophilia and mucus accumulation. This was associated with lower numbers of lung innate lymphocyte cells (ILC2s) and CD4+ T cells producing IL-5+ or IL-13+ and increased IFNγ+ CD4+ and CD8+ T cells, in addition to RSV F-specific CD8+ T cells. These data suggest that in the absence of preimmunity, stabilized PreF antigens may still be associated with aberrant Th2 responses that induce lung pathology in response to RSV infection, and can be prevented by formulation with more Th1/Th2-balanced adjuvants that enhance CD4+ and CD8+ IFNγ+ T cell responses. This may support the use of stabilized PreF antigens with Th1/Th2-balanced adjuvants like, Advax-SM, as safer alternatives to alum in RSV vaccine candidates.


id: cord-296585-yfh5d4io
author: Su, Yu-Ching
date: 2018-11-05
url: https://doi.org/10.3389/fimmu.2018.02530
doi: 10.3389/fimmu.2018.02530
title:
  The Interplay Between Immune Response and Bacterial Infection in COPD: Focus Upon Non-typeable Haemophilus influenzae

abstract:
  Chronic obstructive pulmonary disease (COPD) is a debilitating respiratory disease and one of the leading causes of morbidity and mortality worldwide. It is characterized by persistent respiratory symptoms and airflow limitation due to abnormalities in the lower airway following consistent exposure to noxious particles or gases. Acute exacerbations of COPD (AECOPD) are characterized by increased cough, purulent sputum production, and dyspnea. The AECOPD is mostly associated with infection caused by common cold viruses or bacteria, or co-infections. Chronic and persistent infection by non-typeable Haemophilus influenzae (NTHi), a Gram-negative coccobacillus, contributes to almost half of the infective exacerbations caused by bacteria. This is supported by reports that NTHi is commonly isolated in the sputum from COPD patients during exacerbations. Persistent colonization of NTHi in the lower airway requires a plethora of phenotypic adaptation and virulent mechanisms that are developed over time to cope with changing environmental pressures in the airway such as host immuno-inflammatory response. Chronic inhalation of noxious irritants in COPD causes a changed balance in the lung microbiome, abnormal inflammatory response, and an impaired airway immune system. These conditions significantly provide an opportunistic platform for NTHi colonization and infection resulting in a “vicious circle.” Episodes of large inflammation as the consequences of multiple interactions between airway immune cells and NTHi, accumulatively contribute to COPD exacerbations and may result in worsening of the clinical status. In this review, we discuss in detail the interplay and crosstalk between airway immune residents and NTHi, and their effect in AECOPD for better understanding of NTHi pathogenesis in COPD patients.


id: cord-297790-tpjxt0w5
title: Going to Bat(s) for Studies of Disease Tolerance
author: Mandl, Judith N.
date: 2018-09-20
url: https://doi.org/10.3389/fimmu.2018.02112
doi: 10.3389/fimmu.2018.02112
abstract:
  A majority of viruses that have caused recent epidemics with high lethality rates in people, are zoonoses originating from wildlife. Among them are filoviruses (e.g., Marburg, Ebola), coronaviruses (e.g., SARS, MERS), henipaviruses (e.g., Hendra, Nipah) which share the common features that they are all RNA viruses, and that a dysregulated immune response is an important contributor to the tissue damage and hence pathogenicity that results from infection in humans. Intriguingly, these viruses also all originate from bat reservoirs. Bats have been shown to have a greater mean viral richness than predicted by their phylogenetic distance from humans, their geographic range, or their presence in urban areas, suggesting other traits must explain why bats harbor a greater number of zoonotic viruses than other mammals. Bats are highly unusual among mammals in other ways as well. Not only are they the only mammals capable of powered flight, they have extraordinarily long life spans, with little detectable increases in mortality or senescence until high ages. Their physiology likely impacted their history of pathogen exposure and necessitated adaptations that may have also affected immune signaling pathways. Do our life history traits make us susceptible to generating damaging immune responses to RNA viruses or does the physiology of bats make them particularly tolerant or resistant? Understanding what immune mechanisms enable bats to coexist with RNA viruses may provide critical fundamental insights into how to achieve greater resilience in humans.


id: cord-297960-4x1j0iqg
title: Common Nodes of Virus–Host Interaction Revealed Through an Integrated Network Analysis
author: Bösl, Korbinian
date: 2019-10-04
url: https://doi.org/10.3389/fimmu.2019.02186
doi: 10.3389/fimmu.2019.02186
abstract:
  Viruses are one of the major causes of acute and chronic infectious diseases and thus a major contributor to the global burden of disease. Several studies have shown how viruses have evolved to hijack basic cellular pathways and evade innate immune response by modulating key host factors and signaling pathways. A collective view of these multiple studies could advance our understanding of virus-host interactions and provide new therapeutic perspectives for the treatment of viral diseases. Here, we performed an integrative meta-analysis to elucidate the 17 different host-virus interactomes. Network and bioinformatics analyses showed how viruses with small genomes efficiently achieve the maximal effect by targeting multifunctional and highly connected host proteins with a high occurrence of disordered regions. We also identified the core cellular process subnetworks that are targeted by all the viruses. Integration with functional RNA interference (RNAi) datasets showed that a large proportion of the targets are required for viral replication. Furthermore, we performed an interactome-informed drug re-purposing screen and identified novel activities for broad-spectrum antiviral agents against hepatitis C virus and human metapneumovirus. Altogether, these orthogonal datasets could serve as a platform for hypothesis generation and follow-up studies to broaden our understanding of the viral evasion landscape.


id: cord-298458-p7rvupjo
title: The CD8 T Cell Response to Respiratory Virus Infections
author: Schmidt, Megan E.
date: 2018-04-09
txt: ./txt/cord-298458-p7rvupjo.txt
cache: ./cache/cord-298458-p7rvupjo.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2018.00678
doi: 10.3389/fimmu.2018.00678
summary:
  CD8 T cells play a critical role in mediating viral clearance following many respiratory virus infections including RSV, IAV, and HMPV (25) (26) (27) . In addition, recent murine studies utilizing CD8 T cell epitope-specific immunization strategies observed significantly reduced lung viral titers following IAV, RSV, or SARS challenges (28) (29) (30) . Prime-boosted mice exhibited significantly reduced lung viral titers following RSV, IAV, or SARS infections compared to controls lacking virus-specific memory CD8 T cells. In addition to causing disease in acute respiratory infections, IFN-γ produced by memory CD8 T cells mediated the severe and fatal immunopathology following RSV infection of DC-LM prime-boosted mice (30) . Additionally, robust memory CD8 T cell responses efficiently reduced lung viral titers in the absence of neutralizing antibodies following RSV, IAV, or SARS secondary infections. Despite their benefits in mediating viral clearance and providing protection against secondary infections, memory CD8 T cell responses have been associated with the induction of immunopathology following respiratory virus infections.

abstract:
  Humans are highly susceptible to infection with respiratory viruses including respiratory syncytial virus (RSV), influenza virus, human metapneumovirus, rhinovirus, coronavirus, and parainfluenza virus. While some viruses simply cause symptoms of the common cold, many respiratory viruses induce severe bronchiolitis, pneumonia, and even death following infection. Despite the immense clinical burden, the majority of the most common pulmonary viruses lack long-lasting efficacious vaccines. Nearly all current vaccination strategies are designed to elicit broadly neutralizing antibodies, which prevent severe disease following a subsequent infection. However, the mucosal antibody response to many respiratory viruses is not long-lasting and declines with age. CD8 T cells are critical for mediating clearance following many acute viral infections in the lung. In addition, memory CD8 T cells are capable of providing protection against secondary infections. Therefore, the combined induction of virus-specific CD8 T cells and antibodies may provide optimal protective immunity. Herein, we review the current literature on CD8 T cell responses induced by respiratory virus infections. Additionally, we explore how this knowledge could be utilized in the development of future vaccines against respiratory viruses, with a special emphasis on RSV vaccination.


id: cord-298604-tn8hc6jv
title: Identification of a Novel HIF-1α-α(M)β(2) Integrin-NET Axis in Fibrotic Interstitial Lung Disease
author: Khawaja, Akif A.
date: 2020-10-15
txt: ./txt/cord-298604-tn8hc6jv.txt
cache: ./cache/cord-298604-tn8hc6jv.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.02190
doi: 10.3389/fimmu.2020.02190
summary:
  Finally, we observed NET-like structures in IPF lung sections and in the BAL from ILD patients, and quantification showed increased cell-free DNA content (+5.5-fold, p < 0.01) and MPO-citrullinated histone H3 complexes (+21.9-fold, p < 0.01) in BAL from ILD patients compared to non-ILD controls. Finally, we observed NET-like structures in IPF lung sections and in the BAL from ILD patients, and quantification showed increased cell-free DNA content (+5.5-fold, p < 0.01) and MPO-citrullinated histone H3 complexes (+21.9-fold, p < 0.01) in BAL from ILD patients compared to non-ILD controls. We measured neutrophil adhesion to primary human endothelial cells in the absence or presence of PMA (a general integrin activator) or LPS (to mimic infectious stimuli), stimuli that induce NETs via distinct pathways (42) . We report, for the first time, that neutrophils and endothelial cells in ILD lung biopsies display HIF-1α expression and provide evidence of the extracellular release of nuclear DNA, citrullinated histones and MPO, indicative of NET formation in the ILD lung.

abstract:
  Neutrophilic inflammation correlates with mortality in fibrotic interstitial lung disease (ILD) particularly in the most severe form, idiopathic pulmonary fibrosis (IPF), although the underlying mechanisms remain unclear. Neutrophil function is modulated by numerous factors, including integrin activation, inflammatory cytokines and hypoxia. Hypoxia has an important role in inflammation and may also contribute to pulmonary disease. We aimed to determine how neutrophil activation occurs in ILD and the relative importance of hypoxia. Using lung biopsies and bronchoalveolar lavage (BAL) fluid from ILD patients we investigated the extent of hypoxia and neutrophil activation in ILD lungs. Then we used ex vivo neutrophils isolated from healthy volunteers and BAL from patients with ILD and non-ILD controls to further investigate aberrant neutrophil activation in hypoxia and ILD. We demonstrate for the first time using intracellular staining, HIF-1α stabilization in neutrophils and endothelial cells in ILD lung biopsies. Hypoxia enhanced both spontaneous (+1.31-fold, p < 0.05) and phorbol 12-myristate 13-acetate (PMA)-induced (+1.65-fold, p < 0.001) neutrophil extracellular trap (NET) release, neutrophil adhesion (+8.8-fold, <0.05), and trans-endothelial migration (+1.9-fold, p < 0.05). Hypoxia also increased neutrophil expression of the α(M) (+3.1-fold, p < 0.001) and α(X) (+1.6-fold, p < 0.01) integrin subunits. Interestingly, NET formation was induced by α(M)β(2) integrin activation and prevented by cation chelation. Finally, we observed NET-like structures in IPF lung sections and in the BAL from ILD patients, and quantification showed increased cell-free DNA content (+5.5-fold, p < 0.01) and MPO-citrullinated histone H3 complexes (+21.9-fold, p < 0.01) in BAL from ILD patients compared to non-ILD controls. In conclusion, HIF-1α upregulation may augment neutrophil recruitment and activation within the lung interstitium through activation of β(2) integrins. Our results identify a novel HIF-1α- α(M)β(2) integrin axis in NET formation for future exploration in therapeutic approaches to fibrotic ILD.


id: cord-300429-b0zev8zb
title: Protein Palmitoylation and Its Role in Bacterial and Viral Infections
author: Sobocińska, Justyna
date: 2018-01-19
txt: ./txt/cord-300429-b0zev8zb.txt
cache: ./cache/cord-300429-b0zev8zb.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/29403483/
doi: 10.3389/fimmu.2017.02003
summary:
  We highlight recent data on protein S-palmitoylation in pathogens and their hosts obtained owing to the development of methods based on click chemistry and acyl-biotin exchange allowing proteomic analysis of protein lipidation. Given the large variety of chemical reporters preferentially mimicking distinct fatty acids, recent years have witnessed a plethora of chemistry-based proteomic studies not only on palmitoylated but also myristoylated proteins and proteins bearing the GPI anchor, including those of pathogens and immune cells (10, 14, 85, 86, 114) The aBe Method Reveals Protein The envelope is rich in transmembrane, often S-palmitoylated, glycoproteins called spikes, which can bind to cognate receptors on the host cell plasma membrane triggering endocytosis of the virion, mediate subsequent fusion of the viral and cellular membranes allowing entry of the viral genome to the cytoplasm, and are also involved in the budding of newly formed virus particles from the cell.

abstract:
  S-palmitoylation is a reversible, enzymatic posttranslational modification of proteins in which palmitoyl chain is attached to a cysteine residue via a thioester linkage. S-palmitoylation determines the functioning of proteins by affecting their association with membranes, compartmentalization in membrane domains, trafficking, and stability. In this review, we focus on S-palmitoylation of proteins, which are crucial for the interactions of pathogenic bacteria and viruses with the host. We discuss the role of palmitoylated proteins in the invasion of host cells by bacteria and viruses, and those involved in the host responses to the infection. We highlight recent data on protein S-palmitoylation in pathogens and their hosts obtained owing to the development of methods based on click chemistry and acyl-biotin exchange allowing proteomic analysis of protein lipidation. The role of the palmitoyl moiety present in bacterial lipopolysaccharide and lipoproteins, contributing to infectivity and affecting recognition of bacteria by innate immune receptors, is also discussed.


id: cord-302295-nblmshni
author: Savva, Athina
date: 2013-11-18
url: https://www.ncbi.nlm.nih.gov/pubmed/24302927/
doi: 10.3389/fimmu.2013.00387
title:
  Targeting Toll-Like Receptors: Promising Therapeutic Strategies for the Management of Sepsis-Associated Pathology and Infectious Diseases

abstract:
  Toll-like receptors (TLRs) are pattern recognition receptors playing a fundamental role in sensing microbial invasion and initiating innate and adaptive immune responses. TLRs are also triggered by danger signals released by injured or stressed cells during sepsis. Here we focus on studies developing TLR agonists and antagonists for the treatment of infectious diseases and sepsis. Positioned at the cell surface, TLR4 is essential for sensing lipopolysaccharide of Gram-negative bacteria, TLR2 is involved in the recognition of a large panel of microbial ligands, while TLR5 recognizes flagellin. Endosomal TLR3, TLR7, TLR8, TLR9 are specialized in the sensing of nucleic acids produced notably during viral infections. TLR4 and TLR2 are favorite targets for developing anti-sepsis drugs, and antagonistic compounds have shown efficient protection from septic shock in pre-clinical models. Results from clinical trials evaluating anti-TLR4 and anti-TLR2 approaches are presented, discussing the challenges of study design in sepsis and future exploitation of these agents in infectious diseases. We also report results from studies suggesting that the TLR5 agonist flagellin may protect from infections of the gastrointestinal tract and that agonists of endosomal TLRs are very promising for treating chronic viral infections. Altogether, TLR-targeted therapies have a strong potential for prevention and intervention in infectious diseases, notably sepsis.


id: cord-303017-4zx94rm6
author: Barbieri, Antonio
date: 2020-09-30
url: https://doi.org/10.3389/fimmu.2020.588724
doi: 10.3389/fimmu.2020.588724
title:
  Can Beta-2-Adrenergic Pathway Be a New Target to Combat SARS-CoV-2 Hyperinflammatory Syndrome?—Lessons Learned From Cancer

abstract:
  SARS-CoV-2 infection is a new threat to global public health in the 21(st) century (2020), which has now rapidly spread around the globe causing severe pneumonia often linked to Acute Respiratory Distress Syndrome (ARDS) and hyperinflammatory syndrome. SARS-CoV-2 is highly contagious through saliva droplets. The structural analysis suggests that the virus enters human cells through the ligation of the spike protein to angiotensin-converting enzyme 2 (ACE(2)). The progression of Covid-19 has been divided into three main stages: stage I—viral response, stage II—pulmonary phase, and stage III—hyperinflammation phase. Once the patients enter stage III, it will likely need ventilation and it becomes difficult to manage. Thus, it will be of paramount importance to find therapies to prevent or slow down the progression of the disease toward stage III. The key event leading to hyperinflammation seems to be the activation of Th-17 immunity response and Cytokine storm. B(2)-adrenergic receptors (B(2)ARs) are expressed on airways and on all the immune cells such as macrophages, dendritic cells, B and T lymphocytes. Blocking (B(2)AR) has been proven, also in clinical settings, to reduce Th-17 response and negatively modulate inflammatory cytokines including IL-6 while increasing IFNγ. Non-selective beta-blockers are currently used to treat several diseases and have been proven to reduce stress-induced inflammation and reduce anxiety. For these reasons, we speculate that targeting B(2)AR in the early phase of Covid-19 might be beneficial to prevent hyperinflammation.


id: cord-304619-tpv76833
title: Teaching Immunology as a Liberal Art
author: Chatterjea, Devavani
date: 2020-07-14
txt: ./txt/cord-304619-tpv76833.txt
cache: ./cache/cord-304619-tpv76833.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.01462
doi: 10.3389/fimmu.2020.01462
summary:
  A complex, rapidly evolving biomedical field that is of critical relevance to human health and well-being, immunology provides important and substantive opportunities to practice and teach the central tenets of a liberal arts curriculum. Iteratively learning to read the often dense and technical immunological literature and synthesizing and communicating these findings in their own written and spoken words is both preparation for future work in biomedical fields and a core tenet of a liberal arts education-the importance of listening, reading, speaking, arguing, and writing. However, they also write white papers and reflective essays connecting their learning in immunology to other disciplines, prepare educational materials for community organizations, teach secondary school students and mentor younger peers and, in doing so, practice translating the technical jargon of scientific communication into information that their audiences need and can use. Teaching about our immune systems in integrative, socially relevant ways can help our students make meaningful connections between the content of their learning and the larger global context in which they live.

abstract:
  A complex, rapidly evolving biomedical field that is of critical relevance to human health and well-being, immunology provides important and substantive opportunities to practice and teach the central tenets of a liberal arts curriculum.


id: cord-304623-j9ay4jkf
title: The Veterinary Immunological Toolbox: Past, Present, and Future
author: Entrican, Gary
date: 2020-07-28
txt: ./txt/cord-304623-j9ay4jkf.txt
cache: ./cache/cord-304623-j9ay4jkf.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.01651
doi: 10.3389/fimmu.2020.01651
summary:
  We review the past, present and future of the veterinary immunological toolbox with specific reference to recent developments discussed at the International Union of Immunological Societies (IUIS) Veterinary Immunology Committee (VIC) Immune Toolkit Workshop at the 12th International Veterinary Immunology Symposium (IVIS) in Seattle, USA, 16–19 August 2019. The success of the HLDA workshops was based on good co-ordination, high-quality work and collective effort by the veterinary immunology community, as well as results from past species-specific CD workshops supported by IUIS VIC. A barrier to formal international collaboration was lifted in 2013 when USDA/NIFA and BBSRC launched a pilot call to support animal disease research of strategic importance to both the US and UK which included the development of veterinary immunological reagents for agriculturally-relevant animal species. To date, the concept of the veterinary immunological toolbox has largely (but not exclusively) focused on reagent development for livestock species due to their strategic relevance for funders with a stake in livestock health, food safety and global food security.

abstract:
  It is well-recognized that research capability in veterinary species is restricted by a lack of immunological reagents relative to the extensive toolboxes for small rodent biomedical model species and humans. This creates a barrier to the strategic development of disease control solutions for livestock, companion animals and wildlife that not only affects animal health but can affect human health by increasing the risk of transmission of zoonotic pathogens. There have been a number of projects aimed at reducing the capability gaps in the veterinary immunological toolbox, the majority of these focusing on livestock species. Various approaches have been taken to veterinary immunological reagent development across the globe and technological advances in molecular biology and protein biochemistry have accelerated toolbox development. While short-term funding initiatives can address specific gaps in capability, they do not account for long-term sustainability of reagents and databases that requires a different funding model. We review the past, present and future of the veterinary immunological toolbox with specific reference to recent developments discussed at the International Union of Immunological Societies (IUIS) Veterinary Immunology Committee (VIC) Immune Toolkit Workshop at the 12th International Veterinary Immunology Symposium (IVIS) in Seattle, USA, 16–19 August 2019. The future availability of these reagents is critical to research for improving animal health, responses to infectious pathogens and vaccine design as well as for important analyses of zoonotic pathogens and the animal /human interface for One Health initiatives.


id: cord-304626-ffao7vka
title: Viral Evasion of the Complement System and Its Importance for Vaccines and Therapeutics
author: Mellors, Jack
date: 2020-07-09
txt: ./txt/cord-304626-ffao7vka.txt
cache: ./cache/cord-304626-ffao7vka.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.01450
doi: 10.3389/fimmu.2020.01450
summary:
  A better understanding of this virus-host interplay and its contribution to pathogenesis has previously led to: the identification of genetic factors which influence viral infection and disease outcome, the development of novel antivirals, and the production of safer, more effective vaccines. Infected host cells which present viral antigens on the cell surface membrane can activate the classical pathway, as the antigens bind IgM/IgG to induce complement dependent cytotoxicity (CDC). Non-neutralizing antibodies can still bind the viral target with the potential to cross-link with Fc receptors, or activate complement and interact with complement receptors, to enhance viral infection of host cells (241) . Use of the non-neutralizing influenza virus M2 extracellular vaccine in mice required functional C3 to confer protection and induce effective humoral and cell-mediated immune responses (245) .

abstract:
  The complement system is a key component of innate immunity which readily responds to invading microorganisms. Activation of the complement system typically occurs via three main pathways and can induce various antimicrobial effects, including: neutralization of pathogens, regulation of inflammatory responses, promotion of chemotaxis, and enhancement of the adaptive immune response. These can be vital host responses to protect against acute, chronic, and recurrent viral infections. Consequently, many viruses (including dengue virus, West Nile virus and Nipah virus) have evolved mechanisms for evasion or dysregulation of the complement system to enhance viral infectivity and even exacerbate disease symptoms. The complement system has multifaceted roles in both innate and adaptive immunity, with both intracellular and extracellular functions, that can be relevant to all stages of viral infection. A better understanding of this virus-host interplay and its contribution to pathogenesis has previously led to: the identification of genetic factors which influence viral infection and disease outcome, the development of novel antivirals, and the production of safer, more effective vaccines. This review will discuss the antiviral effects of the complement system against numerous viruses, the mechanisms employed by these viruses to then evade or manipulate this system, and how these interactions have informed vaccine/therapeutic development. Where relevant, conflicting findings and current research gaps are highlighted to aid future developments in virology and immunology, with potential applications to the current COVID-19 pandemic.


id: cord-305936-tdswzj7r
author: Freitas, André Ricardo Ribas
date: 2018-01-08
txt: ./txt/cord-305936-tdswzj7r.txt
cache: ./cache/cord-305936-tdswzj7r.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2017.01903
doi: 10.3389/fimmu.2017.01903
summary:
  Despite not controlling for comorbidities, climate, and vaccination, for the >70 years, ratio of respiratory diseases excess mortality rates between AH1N1 (2009) and severe year of H3N2 (2007) shows protection in the pandemic year and great vulnerability during AH3N2 virus predominance. We analyzed particularly the most predominant variants (AH1N1 and AH3N2) on excess of mortality in the adults and elderly of different age groups in a region with marked seasonality of respiratory diseases in Brazil. Among adults (24-59 years), we observe a large excess of deaths rates during the 2009 pandemic (953 obits), which correspond to 7.1 excess deaths from all causes, and 99 excess mortality from respiratory diseases associated with viral infection in every 100,000 individuals of the age group. Although the elderly are the most vulnerable group to viral respiratory infections, we found relative small excess of deaths in years of circulating AH1N1 pre pandemic (2002 and 2008) .

title:
  Excess of Mortality in Adults and Elderly and Circulation of Subtypes of Influenza Virus in Southern Brazil

abstract:
  PURPOSE: In the elderly population, the influenza infection and its clinical complications are important causes of hospitalization and death, particularly, in longer-lived age. The objective of this study is to analyze the impact of influenza virus circulation on mortality in the elderly and adults, in years with different predominant virus strains. METHODS: We performed a time trend study to evaluated excess of mortality for pneumonia and influenza, respiratory disease, and all-causes in southern region of Brazil, from 2002 to 2015. After considering other models, we opted for Serfling regression. Excess of death rates per 100,000 inhabitants were analyzed in specific age groups (24–59, 60–69, 70–79, ≥80 years) and by year of occurrence. Mortality information were taken from Brazilian Mortality Information System and etiological data were accessed in Sentinel Virological Surveillance database, getting the weekly positivity of the immunofluorescence tests for influenza A (H1N1, H3N2), and B. RESULTS: In southern Brazil, there is an evident seasonal pattern of all death outcomes among different age groups in the dry and cold season (April–September). The highest excess mortality rates occurs among older, particularly in years of circulation of influenza AH3N2, especially among people ≥80 years, in 2003 and 2007—years of great severity of influenza activity. After 2009, with the introduction of the pandemic influenza AH1N1, we observed a lower impact on the mortality of the elderly compared to <60 years. DISCUSSION: A cross reactivity antibody response from past exposure probably provided protection against disease in the elderly. Despite not controlling for comorbidities, climate, and vaccination, for the >70 years, ratio of respiratory diseases excess mortality rates between AH1N1 (2009) and severe year of H3N2 (2007) shows protection in the pandemic year and great vulnerability during AH3N2 virus predominance. CONCLUSION: The reduced immune response to infection, and to vaccination, and presence of comorbidities recommend a special attention to this age group in Brazil. Besides medical assistance, the timeliness of vaccine campaigns, its composition, and etiological surveillance of respiratory diseases are some of the preventive and public health measures.


id: cord-306600-cxz8hf9q
author: Matarazzo, Laura
date: 2019-04-09
txt: ./txt/cord-306600-cxz8hf9q.txt
cache: ./cache/cord-306600-cxz8hf9q.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2019.00723
doi: 10.3389/fimmu.2019.00723
summary:
  Previous studies of the TLR5 agonist flagellin in animal models showed that standalone TLR stimulation does not result in the effective treatment of pneumococcal respiratory infection but does significantly improve the therapeutic outcome of concomitant antibiotic treatment. Previous studies of the TLR5 agonist flagellin in animal models showed that standalone TLR stimulation does not result in the effective treatment of pneumococcal respiratory infection but does significantly improve the therapeutic outcome of concomitant antibiotic treatment. pneumoniae lung infection, we recently demonstrated that combination treatment with mucosally administered flagellin and an orally or intraperitoneally administered low-dose (i.e., subtherapeutic) antibiotic is more effective than the antibiotic alone (i.e., with a lower bacterial load in the lung, and a lower mortality rate). Our data showed that several antimicrobial peptides (S100A9), cytokines (IL-1β and TNF), and chemokines (CCL20, CXCL1, and CXCL2) that were associated to epithelial responses are also upregulated after the administration of the combination treatment in the post-flu superinfection model, suggesting that the epithelium is also an important flagellin-specific driving force in the lung damaged by viral and bacterial infections.

title:
  Therapeutic Synergy Between Antibiotics and Pulmonary Toll-Like Receptor 5 Stimulation in Antibiotic-Sensitive or -Resistant Pneumonia

abstract:
  Bacterial infections of the respiratory tract constitute a major cause of death worldwide. Given the constant rise in bacterial resistance to antibiotics, treatment failure is increasingly frequent. In this context, innovative therapeutic strategies are urgently needed. Stimulation of innate immune cells in the respiratory tract [via activation of Toll-like receptors (TLRs)] is an attractive approach for rapidly activating the body's immune defenses against a broad spectrum of microorganisms. Previous studies of the TLR5 agonist flagellin in animal models showed that standalone TLR stimulation does not result in the effective treatment of pneumococcal respiratory infection but does significantly improve the therapeutic outcome of concomitant antibiotic treatment. Here, we investigated the antibacterial interaction between antibiotic and intranasal flagellin in a mouse model of pneumococcal respiratory infection. Using various doses of orally administered amoxicillin or systemically administered cotrimoxazole, we found that the intranasal instillation of flagellin (a dose that promotes maximal lung pro-inflammatory responses) induces synergistic rather than additive antibacterial effects against antibiotic–susceptible pneumococcus. We next set up a model of infection with pneumococcus that is resistant to multiple antibiotics in the context of influenza superinfection. Remarkably, the combination of amoxicillin and flagellin effectively treated superinfection with the amoxicillin-resistant pneumococcus since the bacterial clearance was increased by more than 100-fold compared to standalone treatments. Our results also showed that, in response to flagellin, the lung tissue generated an innate immune response even though it had been damaged by the influenza virus and pneumococcal infections. In conclusion, we demonstrated that the selective boosting of lung innate immunity is a conceptually advantageous approach for improving the effectiveness of antibiotic treatment and fighting antibiotic-resistant bacteria.


id: cord-307813-elom30nx
title: Advancements in Host-Based Interventions for Influenza Treatment
author: Yip, Tsz-Fung
date: 2018-07-10
txt: ./txt/cord-307813-elom30nx.txt
cache: ./cache/cord-307813-elom30nx.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2018.01547
doi: 10.3389/fimmu.2018.01547
summary:
  Besides controlling virus replication, potential targets for drug development include controlling virus-induced host immune responses such as the recently suggested involvement of innate lymphoid cells and NADPH oxidases in influenza virus pathogenesis and immune cell metabolism. Besides controlling virus replication, potential targets for drug development include controlling virus-induced host immune responses such as the recently suggested involvement of innate lymphoid cells and NADPH oxidases in influenza virus pathogenesis and immune cell metabolism. A recent study using RNAi also demonstrated that cholesterol homeostasis can be regulated via acid phosphatase 2 (ACP2)-mediated Niemann-Pick C2 activity and impaired the membrane fusion of IAV and influenza B virus (IBV) (52) , further suggesting the importance of controlling cholesterol homeostasis in the release of viral genome to cytoplasm. Furthermore, FPR2 antagonists have been described to possess antiviral activity against not only IAV but also IBV infection (111) , promoting the idea that antagonizing FPR2 to suppress Raf/MEK/ERK signaling cascade could potentially be a novel approach for the treatment of a broad spectrum of influenza viruses.

abstract:
  Influenza is a major acute respiratory infection that causes mortality and morbidity worldwide. Two classes of conventional antivirals, M2 ion channel blockers and neuraminidase inhibitors, are mainstays in managing influenza disease to lessen symptoms while minimizing hospitalization and death in patients with severe influenza. However, the development of viral resistance to both drug classes has become a major public health concern. Vaccines are prophylaxis mainstays but are limited in efficacy due to the difficulty in matching predicted dominant viral strains to circulating strains. As such, other potential interventions are being explored. Since viruses rely on host cellular functions to replicate, recent therapeutic developments focus on targeting host factors involved in virus replication. Besides controlling virus replication, potential targets for drug development include controlling virus-induced host immune responses such as the recently suggested involvement of innate lymphoid cells and NADPH oxidases in influenza virus pathogenesis and immune cell metabolism. In this review, we will discuss the advancements in novel host-based interventions for treating influenza disease.


id: cord-308433-vrkdtrfz
title: TNF Blockade Maintains an IL-10(+) Phenotype in Human Effector CD4(+) and CD8(+) T Cells
author: Roberts, Ceri A.
date: 2017-02-15
txt: ./txt/cord-308433-vrkdtrfz.txt
cache: ./cache/cord-308433-vrkdtrfz.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2017.00157
doi: 10.3389/fimmu.2017.00157
summary:
  Addition of the TNFi drug adalimumab to anti-CD3-stimulated human CD4 + T cell/monocyte cocultures led to increased percentages of IL-10 + cells in pro-inflammatory IL-17 + , IFNγ + , TNFα + , GM-CSF + , and IL-4 + CD4 + T cell subpopulations. Addition of the TNFi drug adalimumab to anti-CD3-stimulated human CD4 + T cell/monocyte cocultures led to increased percentages of IL-10 + cells in pro-inflammatory IL-17 + , IFNγ + , TNFα + , GM-CSF + , and IL-4 + CD4 + T cell subpopulations. To investigate whether TNF blockade regulates IL-10 expression in different pro-inflammatory cytokine-producing CD4 + T cells, we isolated CD4 + T cells from PB of healthy donors and cocultured the cells with CD14 + monocytes and anti-CD3 mAb (100 ng/ml) in the absence or presence of the anti-TNF mAb adalimumab (1 µg/ml), as previously described (20) .

abstract:
  CD4(+) and CD8(+) effector T cell subpopulations can display regulatory potential characterized by expression of the prototypically anti-inflammatory cytokine IL-10. However, the underlying cellular mechanisms that regulate expression of IL-10 in different T cell subpopulations are not yet fully elucidated. We recently showed that TNF inhibitors (TNFi) promote IL-10 expression in human CD4(+) T cells, including IL-17(+) CD4(+) T cells. Here, we further characterized the regulation of IL-10 expression via blockade of TNF signaling or other cytokine/co-stimulatory pathways, in human T cell subpopulations. Addition of the TNFi drug adalimumab to anti-CD3-stimulated human CD4(+) T cell/monocyte cocultures led to increased percentages of IL-10(+) cells in pro-inflammatory IL-17(+), IFNγ(+), TNFα(+), GM-CSF(+), and IL-4(+) CD4(+) T cell subpopulations. Conversely, exogenous TNFα strongly decreased IL-10(+) cell frequencies. TNF blockade also regulated IL-10 expression in CD4(+) T cells upon antigenic stimulation. Using time course experiments in whole peripheral blood mononuclear cell (PBMC) cultures, we show that TNF blockade maintained, rather than increased, IL-10(+) cell frequencies in both CD4(+) and CD8(+) T cells following in vitro stimulation in a dose- and time-dependent manner. Blockade of IL-17, IFNγ, IL-6R, or CD80/CD86-mediated co-stimulation did not significantly regulate IL-10 expression within CD4(+) or CD8(+) T cell subpopulations. We show that TNF blockade acts directly on effector CD4(+) T cells, in the absence of monocytes or CD4(+) CD25(high)CD127(low) regulatory T cells and independently of IL-27, resulting in higher IL-10(+) frequencies after 3 days in culture. IL-10/IL-10R blockade reduced the frequency of IL-10-expressing cells both in the presence and absence of TNF blockade. Addition of recombinant IL-10 alone was insufficient to drive an increase in IL-10(+) CD4(+) T cell frequencies in 3-day CD4(+) T cell/monocyte cocultures, but resulted in increased IL-10 expression at later time points in whole PBMC cultures. Together, these data provide additional insights into the regulation of IL-10 expression in human T cells by TNF blockade. The maintenance of an IL-10(+) phenotype across a broad range of effector T cell subsets may represent an underappreciated mechanism of action underlying this widely used therapeutic strategy.


id: cord-312074-0nqmjdek
title: Dipeptidyl Peptidase-4 Regulation of SDF-1/CXCR4 Axis: Implications for Cardiovascular Disease
author: Zhong, Jixin
date: 2015-09-25
txt: ./txt/cord-312074-0nqmjdek.txt
cache: ./cache/cord-312074-0nqmjdek.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2015.00477
doi: 10.3389/fimmu.2015.00477
summary:
  Liebler showed that DPP4 inhibition enhances SDF-1/CXCR4 axis and increased the retention of human bone marrow-derived cells in the injured lungs of immune deficient mice by 30% (71) . It has been shown that parathyroid hormone treatment after myocardial infarction improves DPP4 in chemotaxis and cardiovascular disease Frontiers in Immunology | www.frontiersin.org survival and myocardial function with potential involvement of enhanced homing of bone marrow-derived stem cells. demonstrated that parathyroid hormone serves as a DPP4 inhibitor and increases cardiac SDF-1 level, which in turn enhances CXCR4 + bone marrow-derived stem cell homing to ischemic heart and attenuates ischemic cardiomyopathy after infarction (91) . Suppression of DPP4 enzymatic activities by pharmacological inhibitors preserves SDF-1, which results in an enhanced homing of CXCR4 + progenitor cells from bone marrow to infarcted tissues.

abstract:
  Dipeptidyl peptidase-4 (DPP4) is a ubiquitously expressed protease that regulates diverse number of physiological functions. As a dipeptidase, it exerts its catalytic effects on proteins/peptides with proline, alanine, or serine in the penultimate (P1) amino acid residue from the amino terminus. The evidence to date supports an important effect of DPP4 in catalytic cleavage of incretin peptides and this perhaps represents the main mechanism by which DPP4 inhibition improves glycemic control. DPP4 also plays an important role in the degradation of multiple chemokines of which stromal cell-derived factor-1 (SDF-1, also known as CXCL12) is perhaps an increasingly recognized target, given its importance in processes, such as hematopoiesis, angiogenesis, and stem cell homing. In the current review, we will summarize the importance of DPP4-mediated enzymatic processing of cytokines/chemokines with an emphasis on SDF-1 and resultant implications for cardiovascular physiology and disease.


id: cord-312075-asbt0mcj
title: Viral Evasion Strategies in Type I IFN Signaling – A Summary of Recent Developments
author: Schulz, Katharina S.
date: 2016-11-11
url: https://www.ncbi.nlm.nih.gov/pubmed/27891131/
doi: 10.3389/fimmu.2016.00498
abstract:
  The immune system protects the organism against infections and the damage associated with them. The first line of defense against pathogens is the innate immune response. In the case of a viral infection, it induces the interferon (IFN) signaling cascade and eventually the expression of type I IFN, which then causes an antiviral state in the cells. However, many viruses have developed strategies to counteract this mechanism and prevent the production of IFN. In order to modulate or inhibit the IFN signaling cascade in their favor, viruses have found ways to interfere at every single step of the cascade, for example, by inducing protein degradation or cleavage, or by mediate protein polyubiquitination. In this article, we will review examples of viruses that modulate the IFN response and describe the mechanisms they use.


id: cord-312438-zr9zx7pv
title: Innate Immune Mechanisms to Protect Against Infection at the Human Decidual-Placental Interface
author: Hoo, Regina
date: 2020-09-10
url: https://doi.org/10.3389/fimmu.2020.02070
doi: 10.3389/fimmu.2020.02070
abstract:
  During pregnancy, the placenta forms the anatomical barrier between the mother and developing fetus. Infectious agents can potentially breach the placental barrier resulting in pathogenic transmission from mother to fetus. Innate immune responses, orchestrated by maternal and fetal cells at the decidual-placental interface, are the first line of defense to avoid vertical transmission. Here, we outline the anatomy of the human placenta and uterine lining, the decidua, and discuss the potential capacity of pathogen pattern recognition and other host defense strategies present in the innate immune cells at the placental-decidual interface. We consider major congenital infections that access the placenta from hematogenous or decidual route. Finally, we highlight the challenges in studying human placental responses to pathogens and vertical transmission using current experimental models and identify gaps in knowledge that need to be addressed. We further propose novel experimental strategies to address such limitations.


id: cord-312955-gs65c3fy
title: The Role of Type I Interferons in the Pathogenesis and Treatment of COVID-19
author: Schreiber, Gideon
date: 2020-09-30
txt: ./txt/cord-312955-gs65c3fy.txt
cache: ./cache/cord-312955-gs65c3fy.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.595739
doi: 10.3389/fimmu.2020.595739
summary:
  Although SARS-CoV-2 inhibits the production of IFNβ and thus obstructs the innate immune response to this virus, it is sensitive to the antiviral activity of externally administrated IFN-Is. In this review I discuss the diverse modes of biological actions of IFN-Is and how these are related to biophysical parameters of IFN-I–receptor interaction and cell-type specificity in light of the large variety of binding affinities of the different IFN-I subtypes towards the common interferon receptor. Thereby, it inhibits the nuclear transport of phosphorylated STAT1, rendering cells refractory to IFN-Is. Another example of viral mechanisms that evolved to eliminate IFN-I functions in inducing innate immunity is given by the SARS corona virus, where both the production of IFNb and the IFN-I induced signaling are attenuated. This gene was found to preferentially cleave the ubiquitin-like modifier interferon-stimulated gene 15 (ISG15), FIGURE 4 | SARS-CoV-2 has multiple effects on the immune system, including inhibition of IFNb production, which results in ISGs not to be produced, CD4+ and CD8+ exhaustion and increased levels of pro-inflammatory proteins (TNFa, IL6, NF-kB).

abstract:
  Type I interferons (IFN-I) were first discovered over 60 years ago in a classical experiment by Isaacs and Lindenman, who showed that IFN-Is possess antiviral activity. Later, it became one of the first approved protein drugs using heterologous protein expression systems, which allowed its large-scale production. It has been approved, and widely used in a pleiotropy of diseases, including multiple-sclerosis, hepatitis B and C, and some forms of cancer. Preliminary clinical data has supported its effectiveness against potential pandemic pathogens such as Ebola and SARS. Still, more efficient and specific drugs have taken its place in treating such diseases. The COVID-19 global pandemic has again lifted the status of IFN-Is to become one of the more promising drug candidates, with initial clinical trials showing promising results in reducing the severity and duration of the disease. Although SARS-CoV-2 inhibits the production of IFNβ and thus obstructs the innate immune response to this virus, it is sensitive to the antiviral activity of externally administrated IFN-Is. In this review I discuss the diverse modes of biological actions of IFN-Is and how these are related to biophysical parameters of IFN-I–receptor interaction and cell-type specificity in light of the large variety of binding affinities of the different IFN-I subtypes towards the common interferon receptor. Furthermore, I discuss how these may guide the optimized use IFN-Is in combatting COVID-19.


id: cord-313117-0qur0isb
title: Immune and Metabolic Signatures of COVID-19 Revealed by Transcriptomics Data Reuse
author: Gardinassi, Luiz G.
date: 2020-06-26
txt: ./txt/cord-313117-0qur0isb.txt
cache: ./cache/cord-313117-0qur0isb.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.01636
doi: 10.3389/fimmu.2020.01636
summary:
  To address such issues, recent studies have reported transcriptomic profiles of cells, tissues and fluids from COVID-19 patients that mainly demonstrated activation of humoral immunity, dysregulated type I and III interferon expression, intense innate immune responses and inflammatory signaling. To address such issues, recent studies have reported transcriptomic profiles of cells, tissues and fluids from COVID-19 patients that mainly demonstrated activation of humoral immunity, dysregulated type I and III interferon expression, intense innate immune responses and inflammatory signaling. In addition, our approach also detected increased signals of monocytes (Figure 1B) , dendritic cells ( Figure 1C ) and of the mitochondrial respiratory electron transport chain in SARS-CoV-2 infection (Figure 1A) , suggesting a critical role of metabolic pathways for the immune response of COVID-19 patients.

abstract:
  The current pandemic of coronavirus disease 19 (COVID-19) has affected millions of individuals and caused thousands of deaths worldwide. The pathophysiology of the disease is complex and mostly unknown. Therefore, identifying the molecular mechanisms that promote progression of the disease is critical to overcome this pandemic. To address such issues, recent studies have reported transcriptomic profiles of cells, tissues and fluids from COVID-19 patients that mainly demonstrated activation of humoral immunity, dysregulated type I and III interferon expression, intense innate immune responses and inflammatory signaling. Here, we provide novel perspectives on the pathophysiology of COVID-19 using robust functional approaches to analyze public transcriptome datasets. In addition, we compared the transcriptional signature of COVID-19 patients with individuals infected with SARS-CoV-1 and Influenza A (IAV) viruses. We identified a core transcriptional signature induced by the respiratory viruses in peripheral leukocytes, whereas the absence of significant type I interferon/antiviral responses characterized SARS-CoV-2 infection. We also identified the higher expression of genes involved in metabolic pathways including heme biosynthesis, oxidative phosphorylation and tryptophan metabolism. A BTM-driven meta-analysis of bronchoalveolar lavage fluid (BALF) from COVID-19 patients showed significant enrichment for neutrophils and chemokines, which were also significant in data from lung tissue of one deceased COVID-19 patient. Importantly, our results indicate higher expression of genes related to oxidative phosphorylation both in peripheral mononuclear leukocytes and BALF, suggesting a critical role for mitochondrial activity during SARS-CoV-2 infection. Collectively, these data point for immunopathological features and targets that can be therapeutically exploited to control COVID-19.


id: cord-313227-6zwkfzab
author: Scala, Stefania
date: 2020-05-27
txt: ./txt/cord-313227-6zwkfzab.txt
cache: ./cache/cord-313227-6zwkfzab.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32574268/
doi: 10.3389/fimmu.2020.01201
summary:
  Interestingly, in patients infected by SARS-COv-2, there is an increase in IL1β, IFNγ, IP10, and MCP1, probably leading to activated T-helper-1 (TH1) cell responses, and increased production of T-helper-2 (TH2) immunosuppressive cytokines, such as IL4 and IL10 (18) . Peripheral blood examinations on admission in the majority of patients with COVID-19 displayed lymphopenia, elevated infection-related biomarkers (i.e., procalcitonin, erythrocyte sedimentation rate, serum ferritin, and C-reactive protein) (20) and several elevated inflammatory cytokines (i.e., tumor necrosis factor (TNF)-α, interleukin (IL)-2R and IL-6). Despite markedly reducing virus titers, anti-S-IgG caused lung injury during the early stages of infection, impairing the wound-healing macrophage response and TGF-β production, while promoting pro inflammatory cytokine IL-8, MCP1 production, and inflammatory macrophage accumulation (22) . Another proteasome inhibitor, VR23, possess powerful antiinflammatory activity reducing IL-6 in synovial cells from RA patients, and improving LPS-induced acute lung injury by decreasing neutrophil migration, TNF-α secretion, and tissue inflammation in a mice model (52) .

title:
  Fighting the Host Reaction to SARS-COv-2 in Critically Ill Patients: The Possible Contribution of Off-Label Drugs

abstract:
  The severe acute respiratory syndrome coronavirus 2 (SARS-COv-2) is the etiologic agent of the 2019 coronavirus disease (COVID19). The majority of infected people presents flu like symptoms and among them 15–20% develops a severe interstitial pneumonitis (IP) that may eventually evolve in acute respiratory distress syndrome (ARDS). IP is caused by the viral glycoprotein spike (S) binding to the angiotensin converting enzyme 2 (ACE2) expressed on the surface of alveolar pneumocytes. The virus is recognized by the “pattern recognition receptors” (PRR) of the immune cells that release cytokines activating more immune cells that produce a large number of pro-inflammatory cytokines, tissue factors and vasoactive peptides. Affected patients might develop the “cytokine storm syndrome,” a fulminant and fatal hypercytokinaemia with multiorgan failure. In patients infected by SARS-COv-2 increase in T-helper 2 (TH2) cytokines (IL-4 and IL10) are reported in addition to the T-helper 1 (TH1) cytokines (IL1B, IFNγ, IP10, and MCP1) previously detected in other coronavirus infections. Cytokines and other molecules involved in immune response and inflammation are conceivable therapeutic targets for IP and ARDS, improving symptoms and decreasing intensive care unit admissions. To this aim off label drugs may be used taking into consideration the window timing for immunosuppressive drugs in virus infected patients. Some off label therapeutic options and preclinical evidence drugs are herein considered.


id: cord-313431-swkcdvx8
author: Becerra-Diaz, Mireya
date: 2020-08-07
txt: ./txt/cord-313431-swkcdvx8.txt
cache: ./cache/cord-313431-swkcdvx8.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.01698
doi: 10.3389/fimmu.2020.01698
summary:
  The opposite effects seen in different inflammatory contexts highlight the need for a deeper and broader study of the androgen/ARmediated modulation of monocytes and macrophages, as these cells participate in both the initial and late phases of immune responses in a variety of diseases. Studies of androgen receptor function in human monocytes and macrophages have focused primarily on the roles of male sex and sex hormones in promoting atherosclerotic foam cell formation (196) and inhibiting cutaneous wound healing (186, 215) . There is a paucity of literature regarding how introducing or depleting exogenous sex hormones (such as in female-to-male transgender individuals receiving testosterone supplementation or women with estrogen blockade) affects the function of blood monocytes and lung macrophages in men and women with asthma. Modulation of monocyte and macrophage function mediated by the interaction of androgen and AR has been examined mostly by correlative studies in humans following lifespan changes in sex hormones or using hormonal manipulation in mouse models of lung disease.

title:
  Androgen and Androgen Receptors as Regulators of Monocyte and Macrophage Biology in the Healthy and Diseased Lung

abstract:
  Androgens, the predominant male sex hormones, drive the development and maintenance of male characteristics by binding to androgen receptor (AR). As androgens are systemically distributed throughout the whole organism, they affect many tissues and cell types in addition to those in male sexual organs. It is now clear that the immune system is a target of androgen action. In the lungs, many immune cells express ARs and are responsive to androgens. In this review, we describe the effects of androgens and ARs on lung myeloid immune cells—monocytes and macrophages—as they relate to health and disease. In particular, we highlight the effect of androgens on lung diseases, such as asthma, chronic obstructive pulmonary disease and lung fibrosis. We also discuss the therapeutic use of androgens and how circulating androgens correlate with lung disease. In addition to human studies, we also discuss how mouse models have helped to uncover the effect of androgens on monocytes and macrophages in lung disease. Although the role of estrogen and other female hormones has been broadly analyzed in the literature, we focus on the new perspectives of androgens as modulators of the immune system that target myeloid cells during lung inflammation.


id: cord-316702-dj2fo8sn
title: Is Herd Immunity Against SARS-CoV-2 a Silver Lining?
author: Vignesh, Ramachandran
date: 2020-09-30
txt: ./txt/cord-316702-dj2fo8sn.txt
cache: ./cache/cord-316702-dj2fo8sn.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33101320/
doi: 10.3389/fimmu.2020.586781
abstract: nan
summary:
  Since many studies from different geographical locations are documenting preexisting immunity to SARS-CoV-2, it will be important to define specificities of these T and B cell immune response carefully to assess their association with COVID-19 disease severity. This preexisting cross-reactive T and B cell immunity to SARS-CoV-2 may have wide implications as this could explain differential clinical outcomes in COVID-19 patients, disease severity, vaccine development, and important in accessing herd immunity for SARS-CoV-2 viral infection/COVID-19 disease. Several studies have provided strong evidence for the importance of SARS-CoV-2 specific CTLs, and T helper cells in mild and moderate patients compared to severe COVID-19 disease (27, 28, (31) (32) (33) . Several studies have provided strong evidence for the importance of SARS-CoV-2specific neutralizing antibodies in association with less disease severity in COVID-19 patients (38, 39) . A recent modelling study has estimated that about one in five individuals worldwide would be at increased risk of severe COVID-19, upon infection with SARS-CoV-2, owing to the underlying conditions.


id: cord-317797-h229skaq
title: Crosstalk Between Platelets and Microbial Pathogens
author: Li, Conglei
date: 2020-08-07
txt: ./txt/cord-317797-h229skaq.txt
cache: ./cache/cord-317797-h229skaq.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.01962
doi: 10.3389/fimmu.2020.01962
summary:
  For example, thrombocytopenia in children following varicella zoster virus infection first described antigenic mimicry for some microbial pathogens that encompass host generation of crossreactive antibodies to certain glycoproteins (e.g., GPIIIa) on the platelet surface, resulting in accelerated platelet clearance (117) . In addition to the effects on platelet count and function, microbial pathogens impact the host auto-and alloimmune response to platelet antigens in several immune-mediated diseases, such as immune thrombocytopenia (ITP), and fetal and neonatal alloimmune thrombocytopenia (FNAIT) (99-101) (Figure 3) . C-reactive protein is markedly upregulated during acute infections and inflammation (178) , and it has been shown that C-reactive protein, via binding to platelet phosphorylcholine residues, enhanced the IgG-mediated phagocytic responses against platelets and thereby thrombocytopenia, which has implications in the pathogenesis of both ITP and FNAIT (123, 124) .

abstract:
  Platelets, small anucleate cells circulating in the blood, are critical mediators in haemostasis and thrombosis. Interestingly, recent studies demonstrated that platelets contain both pro-inflammatory and anti-inflammatory molecules, equipping platelets with immunoregulatory function in both innate and adaptive immunity. In the context of infectious diseases, platelets are involved in early detection of invading microorganisms and are actively recruited to sites of infection. Platelets exert their effects on microbial pathogens either by direct binding to eliminate or restrict dissemination, or by shaping the subsequent host immune response. Reciprocally, many invading microbial pathogens can directly or indirectly target host platelets, altering platelet count or/and function. In addition, microbial pathogens can impact the host auto- and alloimmune responses to platelet antigens in several immune-mediated diseases, such as immune thrombocytopenia, and fetal and neonatal alloimmune thrombocytopenia. In this review, we discuss the mechanisms that contribute to the bidirectional interactions between platelets and various microbial pathogens, and how these interactions hold relevant implications in the pathogenesis of many infectious diseases. The knowledge obtained from “well-studied” microbes may also help us understand the pathogenesis of emerging microbes, such as SARS-CoV-2 coronavirus.


id: cord-318418-uqxzds6g
author: Inatomi, Takio
date: 2017-12-22
txt: ./txt/cord-318418-uqxzds6g.txt
cache: ./cache/cord-318418-uqxzds6g.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/29312349/
doi: 10.3389/fimmu.2017.01877
summary:
  title: Dietary Probiotic Compound Improves Reproductive Performance of Porcine Epidemic Diarrhea Virus-Infected Sows Reared in a Japanese Commercial Swine Farm under Vaccine Control Condition Hence, here we evaluated the efficacy of administration of a probiotic compound containing Bacillus mesentericus, Clostridium butyricum, and Enterococcus faecalis together with a commercial live-attenuated PED vaccine (Nisseiken PED Live Vaccine, Nisseiken, Tokyo, Japan) to improve the health and reproductive performance of PED-infected sows. The aim of the present study was to evaluate the efficacy of the aforementioned probiotic compound mixed with peptide-zinc to improve the health and reproductive performance of PEDinfected lactating sows when administered along with a PED vaccine injection in Japan. Nonetheless, in the present work, probiotics supplementation significantly improved the concentration of total IgA and IgG in the milk of sows than did PED vaccination alone, possibly resulting from stimulation of gut immunity by bacteria in the administered probiotic compound (Figures 5A,B) .

title:
  Dietary Probiotic Compound Improves Reproductive Performance of Porcine Epidemic Diarrhea Virus-Infected Sows Reared in a Japanese Commercial Swine Farm under Vaccine Control Condition

abstract:
  Lactogenic immunity transferred to piglets after inoculation of a live vaccine to pregnant sows was proved limited to control porcine epidemic diarrhea (PED). Hence, here we evaluated the efficacy of administration of a probiotic compound containing Bacillus mesentericus, Clostridium butyricum, and Enterococcus faecalis together with a commercial live-attenuated PED vaccine (Nisseiken PED Live Vaccine, Nisseiken, Tokyo, Japan) to improve the health and reproductive performance of PED-infected sows. Twenty pregnant sows in a PED-positive farm were equally divided into probiotics-administered (VP) and control (VC) sow groups. A commercial live-attenuated vaccine was injected as per the manufacturer’s instruction. The probiotic compound (15 g/day) was orally administered to VP from 6 weeks pre-parturition to 7 days post-parturition (ppd7). VP had a significantly higher body weight at ppd7 than VC (191 vs 186 kg; P < 0.05). At day 3 post-parturition (ppd3) (4.18 vs 3.63 kg/day) and ppd7 (5.14 vs 4.34 kg/day), milk produced by VP was significantly (P < 0.05) greater than that by VC. Total immunoglobulin (Ig)A and IgG concentrations at day 0 were significantly (P < 0.05) higher in whey of VP (1.9 and 6.6 g/dL, respectively) than in that of VC (1.7 and 6.1 g/dL, respectively). However, total IgG concentration in whey of VP and VC at ppd3 and ppd7 did not differ. Antibody titer was significantly higher at day 0 in serum of VP than it was that of VC (60 vs 37 in geometric mean; P < 0.05). Likewise, the antibody titer in whey of VP and VC was found to be similar at day 0 (416 vs 208 in geometric mean; P = 0.13). Consequently, VP had fewer days between weaning and return to estrus than did VC (7 vs 10 days; P < 0.05). Moreover, piglets of VP had a significantly (P < 0.05) higher litter weight at birth (9,252 g/litter) and a lower mortality (12%) during suckling than those of VC (8,686 g/litter and 28%, respectively). In summary, probiotic-supplemented, PED-vaccinated sows were healthier, transferred PED-specific antibodies via colostrum to piglets, had greater litter weight at birth, and reduced mortality during suckling.


id: cord-318630-h6j7iqbm
title: CD8(+) T-Cells as Immune Regulators of Multiple Sclerosis
author: Sinha, Sushmita
date: 2015-12-10
txt: ./txt/cord-318630-h6j7iqbm.txt
cache: ./cache/cord-318630-h6j7iqbm.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2015.00619
doi: 10.3389/fimmu.2015.00619
summary:
  In our studies, we have shown that cytotoxic/suppressor CD8(+) T-cells are CNS antigen-specific, MHC class I-restricted, IFNγand perforin-dependent, and are able to inhibit disease. iNTRODUCTiON Studies addressing the immunobiology of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) have focused on CD4 + T-cells as the main orchestrators of pathogenesis and regulation. Interestingly, immune deviation can be elicited against myelin antigens (61, 62) , pointing to the potential role for Qa-1-restricted CD8 + T-cells in EAE disease. We have also demonstrated that GA treatment induces CD8 + Treg in mice, and that these CD8 + T-cells are required for GA to be therapeutically effective in ameliorating EAE disease (64) . Furthermore, relapses in MS are associated with significantly lower CNS-specific CD8 + T-cell suppressor ability, while this potential in MS patients during quiescence is similar to healthy donors, suggesting a role with disease activity (5) .

abstract:
  The vast majority of studies regarding the immune basis of MS (and its animal model, EAE) have largely focused on CD4(+) T-cells as mediators and regulators of disease. Interestingly, CD8(+) T-cells represent the predominant T-cell population in human MS lesions and are oligoclonally expanded at the site of pathology. However, their role in the autoimmune pathologic process has been both understudied and controversial. Several animal models and MS patient studies support a pathogenic role for CNS-specific CD8(+) T-cells, whereas we and others have demonstrated a regulatory role for these cells in disease. In this review, we describe studies that have investigated the role of CD8(+) T-cells in MS and EAE, presenting evidence for both pathogenic and regulatory functions. In our studies, we have shown that cytotoxic/suppressor CD8(+) T-cells are CNS antigen-specific, MHC class I-restricted, IFNγ- and perforin-dependent, and are able to inhibit disease. The clinical relevance for CD8(+) T-cell suppressive function is best described by a lack of their function during MS relapse, and importantly, restoration of their suppressive function during quiescence. Furthermore, CD8(+) T-cells with immunosuppressive functions can be therapeutically induced in MS patients by glatiramer acetate (GA) treatment. Unlike CNS-specific CD8(+) T-cells, these immunosuppressive GA-induced CD8(+) T-cells appear to be HLA-E restricted. These studies have provided greater fundamental insight into the role of autoreactive as well as therapeutically induced CD8(+) T-cells in disease amelioration. The clinical implications for these findings are immense and we propose that this natural process can be harnessed toward the development of an effective immunotherapeutic strategy.


id: cord-319729-6lzjhn8j
author: Tian, Bin
date: 2018-01-19
txt: ./txt/cord-319729-6lzjhn8j.txt
cache: ./cache/cord-319729-6lzjhn8j.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2017.02011
doi: 10.3389/fimmu.2017.02011
summary:
  title: Lab-Attenuated Rabies Virus Causes Abortive Infection and Induces Cytokine Expression in Astrocytes by Activating Mitochondrial Antiviral-Signaling Protein Signaling Pathway Activation of mitochondrial antiviral-signaling protein (MAVS), the common adaptor molecule for RIG-I and MDA5, results in the production of type I interferon (IFN) and the expression of hundreds of IFN-stimulated genes, which suppress RABV replication and spread in astrocytes. Activation of mitochondrial antiviral-signaling protein (MAVS), the common adaptor molecule for RIG-I and MDA5, results in the production of type I interferon (IFN) and the expression of hundreds of IFN-stimulated genes, which suppress RABV replication and spread in astrocytes. To assess innate immune responses in astrocytes, cells were infected with DRV or B2c at an MOI of 0.1 and the expression of several proteins involved in the MAVS signaling pathway, namely, RIG-I, p-IRF7, STAT1 and IFIT1 (ISG56), was measured by Western blot.

title:
  Lab-Attenuated Rabies Virus Causes Abortive Infection and Induces Cytokine Expression in Astrocytes by Activating Mitochondrial Antiviral-Signaling Protein Signaling Pathway

abstract:
  Rabies is an ancient disease but remains endemic in most parts of the world and causes approximately 59,000 deaths annually. The mechanism through which the causative agent, rabies virus (RABV), evades the host immune response and infects the host central nervous system (CNS) has not been completely elucidated thus far. Our previous studies have shown that lab-attenuated, but not wild-type (wt), RABV activates the innate immune response in the mouse and dog models. In this present study, we demonstrate that lab-attenuated RABV causes abortive infection in astrocytes, the most abundant glial cells in the CNS. Furthermore, we found that lab-attenuated RABV produces more double-stranded RNA (dsRNA) than wt RABV, which is recognized by retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated protein 5 (MDA5). Activation of mitochondrial antiviral-signaling protein (MAVS), the common adaptor molecule for RIG-I and MDA5, results in the production of type I interferon (IFN) and the expression of hundreds of IFN-stimulated genes, which suppress RABV replication and spread in astrocytes. Notably, lab-attenuated RABV replicates in a manner identical to that of wt RABV in MAVS−/− astrocytes. It was also found that lab-attenuated, but not wt, RABV induces the expression of inflammatory cytokines via the MAVS- p38/NF-κB signaling pathway. These inflammatory cytokines increase the blood–brain barrier permeability and thus enable immune cells and antibodies infiltrate the CNS parenchyma, resulting in RABV control and elimination. In contrast, wt RABV restricts dsRNA production and thus evades innate recognition by RIG-I/MDA5 in astrocytes, which could be one of the mechanisms by which wt RABV evades the host immune response in resident CNS cells. Our findings suggest that astrocytes play a critical role in limiting the replication of lab-attenuated RABV in the CNS.


id: cord-319774-mkz7z38o
title: High-Throughput Sequencing-Based Immune Repertoire Study during Infectious Disease
author: Hou, Dongni
date: 2016-08-31
txt: ./txt/cord-319774-mkz7z38o.txt
cache: ./cache/cord-319774-mkz7z38o.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2016.00336
doi: 10.3389/fimmu.2016.00336
summary:
  The selectivity of the adaptive immune response is based on the enormous diversity of T and B cell antigen-specific receptors. During the past two decades, however, technical advances in high-throughput sequencing (HTS), also known as next-generation sequencing (NGS), along with evolving bioinformatic and statistical tools, have provided a new approach capable of analyzing the immune repertoire at the single sequence level. The depth and comprehensiveness of high-throughput immune repertoire sequencing are greater than ever, and the enormous sequencing data of disease-specific TCR/BCR clones provide great potential for the revealing dynamic changes in clonality during infectious states. Decrease in the overall diversity of the immune repertoire have been observed after various antigen exposures, including HIV, influenza, and human herpes virus, which implies expansion of particular T/B cell clones (67, 88, 92, 93) . Pairing the heavy and light chains as an integrated antibody has been another challenge for HTS-based immune repertoire analysis.

abstract:
  The selectivity of the adaptive immune response is based on the enormous diversity of T and B cell antigen-specific receptors. The immune repertoire, the collection of T and B cells with functional diversity in the circulatory system at any given time, is dynamic and reflects the essence of immune selectivity. In this article, we review the recent advances in immune repertoire study of infectious diseases, which were achieved by traditional techniques and high-throughput sequencing (HTS) techniques. HTS techniques enable the determination of complementary regions of lymphocyte receptors with unprecedented efficiency and scale. This progress in methodology enhances the understanding of immunologic changes during pathogen challenge and also provides a basis for further development of novel diagnostic markers, immunotherapies, and vaccines.


id: cord-320431-0877trhh
title: More Than Just a Barrier: The Immune Functions of the Airway Epithelium in Asthma Pathogenesis
author: Frey, Andreas
date: 2020-04-28
txt: ./txt/cord-320431-0877trhh.txt
cache: ./cache/cord-320431-0877trhh.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.00761
doi: 10.3389/fimmu.2020.00761
summary:
  In case of asthma, all these functions are impaired by the already existing allergic immune response that per se weakens the barrier integrity and self-cleaning abilities of the airway epithelium making it more vulnerable to penetration of allergens as well as of infection by bacteria and viruses. Besides this innate "rapid response team, " the polarized epithelium of the human airways is also able to transport and apically release immunoglobulins that carry a J-chain (joining chain) by using its poly Ig receptor (pIgR) (145) (146) (147) that is expressed by all non-stratified epithelial cells (Figure 2) . After contact for example with HDM extracts, representing a major source of asthma associated allergens, TLR4 dependent activation of NFκB and protease induced injuries in airway epithelial cells lead to secretion of chemokines and cytokines like thymic stromal lymphopoietin (TSLP), GM-CSF, IL-25, and IL-33 (211) (212) (213) (214) (215) .

abstract:
  Allergic bronchial asthma is a chronic disease of the airways that is characterized by symptoms like respiratory distress, chest tightness, wheezing, productive cough, and acute episodes of broncho-obstruction. This symptom-complex arises on the basis of chronic allergic inflammation of the airway wall. Consequently, the airway epithelium is central to the pathogenesis of this disease, because its multiple abilities directly have an impact on the inflammatory response and thus the formation of the disease. In turn, its structure and functions are markedly impaired by the inflammation. Hence, the airway epithelium represents a sealed, self-cleaning barrier, that prohibits penetration of inhaled allergens, pathogens, and other noxious agents into the body. This barrier is covered with mucus that further contains antimicrobial peptides and antibodies that are either produced or specifically transported by the airway epithelium in order to trap these particles and to remove them from the body by a process called mucociliary clearance. Once this first line of defense of the lung is overcome, airway epithelial cells are the first cells to get in contact with pathogens, to be damaged or infected. Therefore, these cells release a plethora of chemokines and cytokines that not only induce an acute inflammatory reaction but also have an impact on the alignment of the following immune reaction. In case of asthma, all these functions are impaired by the already existing allergic immune response that per se weakens the barrier integrity and self-cleaning abilities of the airway epithelium making it more vulnerable to penetration of allergens as well as of infection by bacteria and viruses. Recent studies indicate that the history of allergy- and pathogen-derived insults can leave some kind of memory in these cells that can be described as imprinting or trained immunity. Thus, the airway epithelium is in the center of processes that lead to formation, progression and acute exacerbation of asthma.


id: cord-320474-jyk7zphp
title: Targeting GM-CSF in COVID-19 Pneumonia: Rationale and Strategies
author: Bonaventura, Aldo
date: 2020-07-03
txt: ./txt/cord-320474-jyk7zphp.txt
cache: ./cache/cord-320474-jyk7zphp.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32719685/
doi: 10.3389/fimmu.2020.01625
summary:
  Initial findings from patients with COVID-19 treated with a single intravenous dose of mavrilimumab, a monoclonal antibody binding GM-CSF receptor α, showed oxygenation improvement and shorter hospitalization. Data supporting the role of hyperinflammation in sepsisrelated acute respiratory distress syndrome (ARDS) are derived from a sub-group analysis of a phase 3 randomized controlled trial of IL-1 receptor antagonist (anakinra), which showed significant survival benefit in patients treated with anakinra compared to placebo (15) . APC, antigen presenting cell; DC, dendritic cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. A randomized, double-blind, placebo-controlled phase II study tested the effects of low-dose hrGM-CSF (molgramostim, 3 µg/kg daily) for 5 days in patients in addition to the standard of care in critically ill patients with severe sepsis and respiratory dysfunction (65) .

abstract:
  COVID-19 is a clinical syndrome ranging from mild symptoms to severe pneumonia that often leads to respiratory failure, need for mechanical ventilation, and death. Most of the lung damage is driven by a surge in inflammatory cytokines [interleukin-6, interferon-γ, and granulocyte-monocyte stimulating factor (GM-CSF)]. Blunting this hyperinflammation with immunomodulation may lead to clinical improvement. GM-CSF is produced by many cells, including macrophages and T-cells. GM-CSF-derived signals are involved in differentiation of macrophages, including alveolar macrophages (AMs). In animal models of respiratory infections, the intranasal administration of GM-CSF increased the proliferation of AMs and improved outcomes. Increased levels of GM-CSF have been recently described in patients with COVID-19 compared to healthy controls. While GM-CSF might be beneficial in some circumstances as an appropriate response, in this case the inflammatory response is maladaptive by virtue of being later and disproportionate. The inhibition of GM-CSF signaling may be beneficial in improving the hyperinflammation-related lung damage in the most severe cases of COVID-19. This blockade can be achieved through antagonism of the GM-CSF receptor or the direct binding of circulating GM-CSF. Initial findings from patients with COVID-19 treated with a single intravenous dose of mavrilimumab, a monoclonal antibody binding GM-CSF receptor α, showed oxygenation improvement and shorter hospitalization. Prospective, randomized, placebo-controlled trials are ongoing. Anti-GM-CSF monoclonal antibodies, TJ003234 and gimsilumab, will be tested in clinical trials in patients with COVID-19, while lenzilumab received FDA approval for compassionate use. These trials will help inform whether blunting the inflammatory signaling provided by the GM-CSF axis in COVID-19 is beneficial.


id: cord-320663-xypg6evo
title: Flattening the COVID-19 Curve With Natural Killer Cell Based Immunotherapies
author: Market, Marisa
date: 2020-06-23
url: https://doi.org/10.3389/fimmu.2020.01512
doi: 10.3389/fimmu.2020.01512
abstract:
  Natural Killer (NK) cells are innate immune responders critical for viral clearance and immunomodulation. Despite their vital role in viral infection, the contribution of NK cells in fighting SARS-CoV-2 has not yet been directly investigated. Insights into pathophysiology and therapeutic opportunities can therefore be inferred from studies assessing NK cell phenotype and function during SARS, MERS, and COVID-19. These studies suggest a reduction in circulating NK cell numbers and/or an exhausted phenotype following infection and hint toward the dampening of NK cell responses by coronaviruses. Reduced circulating NK cell levels and exhaustion may be directly responsible for the progression and severity of COVID-19. Conversely, in light of data linking inflammation with coronavirus disease severity, it is necessary to examine NK cell potential in mediating immunopathology. A common feature of coronavirus infections is that significant morbidity and mortality is associated with lung injury and acute respiratory distress syndrome resulting from an exaggerated immune response, of which NK cells are an important component. In this review, we summarize the current understanding of how NK cells respond in both early and late coronavirus infections, and the implication for ongoing COVID-19 clinical trials. Using this immunological lens, we outline recommendations for therapeutic strategies against COVID-19 in clearing the virus while preventing the harm of immunopathological responses.


id: cord-321401-w4ne60fn
author: Schrumpf, Jasmijn A.
date: 2020-07-10
txt: ./txt/cord-321401-w4ne60fn.txt
cache: ./cache/cord-321401-w4ne60fn.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32754156/
doi: 10.3389/fimmu.2020.01433
summary:
  Evidence for this immunomodulatory and protective role is derived from observational studies showing an association between vitamin D deficiency, chronic airway diseases and respiratory infections, and is supported by a range of experimental studies using cell culture and animal models. Furthermore, recent intervention studies have now shown that vitamin D supplementation reduces exacerbation rates in vitamin D-deficient patients with chronic obstructive pulmonary disease (COPD) or asthma and decreases the incidence of acute respiratory tract infections. Increasing evidence has indicated that vitamin D deficiency is also associated with various other diseases such as cancer, cardiovascular disease, Alzheimer''s disease and muscle myopathy, as well as several immune-related diseases such as type 1 diabetes, multiple sclerosis, inflammatory bowel disease (IBD), psoriasis and chronic inflammatory lung diseases including asthma, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD) (6) (7) (8) (9) .

title:
  Impact of the Local Inflammatory Environment on Mucosal Vitamin D Metabolism and Signaling in Chronic Inflammatory Lung Diseases

abstract:
  Vitamin D plays an active role in the modulation of innate and adaptive immune responses as well as in the protection against respiratory pathogens. Evidence for this immunomodulatory and protective role is derived from observational studies showing an association between vitamin D deficiency, chronic airway diseases and respiratory infections, and is supported by a range of experimental studies using cell culture and animal models. Furthermore, recent intervention studies have now shown that vitamin D supplementation reduces exacerbation rates in vitamin D-deficient patients with chronic obstructive pulmonary disease (COPD) or asthma and decreases the incidence of acute respiratory tract infections. The active vitamin D metabolite, 1,25-dihydroxy-vitamin D (1,25(OH)(2)D), is known to contribute to the integrity of the mucosal barrier, promote killing of pathogens (via the induction of antimicrobial peptides), and to modulate inflammation and immune responses. These mechanisms may partly explain its protective role against infections and exacerbations in COPD and asthma patients. The respiratory mucosa is an important site of local 1,25(OH)(2)D synthesis, degradation and signaling, a process that can be affected by exposure to inflammatory mediators. As a consequence, mucosal inflammation and other disease-associated factors, as observed in e.g., COPD and asthma, may modulate the protective actions of 1,25(OH)(2)D. Here, we discuss the potential consequences of various disease-associated processes such as inflammation and exposure to pathogens and inhaled toxicants on vitamin D metabolism and local responses to 1,25(OH)(2)D in both immune- and epithelial cells. We furthermore discuss potential consequences of disturbed local levels of 25(OH)D and 1,25(OH)(2)D for chronic lung diseases. Additional insight into the relationship between disease-associated mechanisms and local effects of 1,25(OH)(2)D is expected to contribute to the design of future strategies aimed at improving local levels of 1,25(OH)(2)D and signaling in chronic inflammatory lung diseases.


id: cord-321568-okvt1fg3
title: Perspective: The Potential Effects of Naringenin in COVID-19
author: Alberca, Ricardo Wesley
date: 2020-09-25
url: https://www.ncbi.nlm.nih.gov/pubmed/33101291/
doi: 10.3389/fimmu.2020.570919
abstract:
  Coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), was declared a pandemic by the World Health Organization in March 2020. Severe COVID-19 cases develop severe acute respiratory syndrome, which can result in multiple organ failure, sepsis, and death. The higher risk group includes the elderly and subjects with pre-existing chronic illnesses such as obesity, hypertension, and diabetes. To date, no specific treatment or vaccine is available for COVID-19. Among many compounds, naringenin (NAR) a flavonoid present in citrus fruits has been investigated for antiviral and anti-inflammatory properties like reducing viral replication and cytokine production. In this perspective, we summarize NAR potential anti-inflammatory role in COVID-19 associated risk factors and SARS-CoV-2 infection.


id: cord-323590-m4jsu1q5
author: Ortiz de Landazuri, Iñaki
date: 2020-10-15
txt: ./txt/cord-323590-m4jsu1q5.txt
cache: ./cache/cord-323590-m4jsu1q5.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.573179
doi: 10.3389/fimmu.2020.573179
summary:
  The COVID-19 pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has generated a significant repercussion on the administration of adoptive cell therapies, including chimeric antigen receptor (CAR) T-cells. The aim of this mini-review is to focus on how the COVID-19 pandemic has affected CAR T-cell therapy and taking into consideration the differences between the large-scale centralized productions for the pharmaceutical industry versus product manufacturing in the academic/hospital environment. Therefore, the aim of this mini-review is to focus on how the effects caused by the pandemic have affected this therapy taking into consideration the differences between the large-scale centralized production of CAR T-cells by the pharmaceutical industry versus the product manufacturing processes employed by the academic/hospital environment. We also review different aspects of CAR T-cell therapy, including patient selection and resource prioritization performed in our center during the COVID-19 pandemic.

title:
  Manufacturing and Management of CAR T-Cell Therapy in “COVID-19’s Time”: Central Versus Point of Care Proposals

abstract:
  The COVID-19 pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has generated a significant repercussion on the administration of adoptive cell therapies, including chimeric antigen receptor (CAR) T-cells. The closing of borders, the reduction of people transit and the confinement of the population has affected the supply chains of these life-saving medical products. The aim of this mini-review is to focus on how the COVID-19 pandemic has affected CAR T-cell therapy and taking into consideration the differences between the large-scale centralized productions for the pharmaceutical industry versus product manufacturing in the academic/hospital environment. We also review different aspects of CAR T-cell therapy and our managerial experience of patient selection, resource prioritization and some practical aspects to consider for safe administration. Although hospitals have been forced to change their usual workflows to cope with the saturation of health services by hospitalized patients, we recommend centers to continue offering this potentially curative treatment for patients with relapsed/refractory hematologic malignancies. Consequently, we propose appropriate selection criteria, early intervention to attenuate neurotoxicity or cytokine release syndrome with tocilizumab and prophylactic/preventive strategies to prevent infection. These considerations may apply to other emerging adoptive cell treatments and the corresponding manufacturing processes.


id: cord-323756-atnrw9ew
title: Sensing Microbial RNA in the Cytosol
author: Vabret, Nicolas
date: 2013-12-25
txt: ./txt/cord-323756-atnrw9ew.txt
cache: ./cache/cord-323756-atnrw9ew.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/24400006/
doi: 10.3389/fimmu.2013.00468
summary:
  When Janeway formulated the theory of pattern recognition in 1989, he proposed that host cells could sense microbial infection owing to receptors able to recognize invariant molecular structures defined as pathogen-associated molecular patterns (PAMPs). They share a similar organization with three distinct domains: (i) a C-terminal repressor domain (RD) embedded within the C-terminal domain (CTD); (ii) a central ATPase containing DExD/H-box helicase domain able to bind RNA; and (iii) a N-terminal tandem CARD domain that mediates downstream signaling, and which is present in RIG-I and MDA5 but absent in LGP2. DDX60 has also been shown to enhance the IFN-I response to RNA and DNA stimulation through formation of complexes with Frontiers in Immunology | Molecular Innate Immunity RIG-I, MDA5, and LGP2 but not with MAVS. Structural basis for the activation of innate immune pattern-recognition receptor RIG-I by viral RNA Nonself RNA-sensing mechanism of RIG-I helicase and activation of antiviral immune responses

abstract:
  The innate immune system faces the difficult task of keeping a fine balance between sensitive detection of microbial presence and avoidance of autoimmunity. To this aim, key mechanisms of innate responses rely on isolation of pathogens in specialized subcellular compartments, or sensing of specific microbial patterns absent from the host. Efficient detection of foreign RNA in the cytosol requires an additional layer of complexity from the immune system. In this particular case, innate sensors should be able to distinguish self and non-self molecules that share several similar properties. In this review, we discuss this interplay between cytosolic pattern recognition receptors and the microbial RNA they detect. We describe how microbial RNAs gain access to the cytosol, which receptors they activate and counter-strategies developed by microorganisms to avoid this response.


id: cord-325129-faptufak
title: Understanding the Pathophysiology of COVID-19: Could the Contact System Be the Key?
author: Meini, Simone
date: 2020-08-11
txt: ./txt/cord-325129-faptufak.txt
cache: ./cache/cord-325129-faptufak.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32849666/
doi: 10.3389/fimmu.2020.02014
summary:
  Autoactivation of FXII by contact with SARS-CoV-2 could lead to activation of intrinsic coagulation, with fibrin formation (microthrombosis), and fibrinolysis, resulting in increased D-dimer levels. In this review, we try to address the complex link between the pathophysiology of COVID-19 and the different proteolytic defense systems operating in human vasculature, investigating the role of the mediators involved and speculating on the possibility of pharmacological modulation. After binding through its B2R, BK activates signaling pathways resulting in increased vascular permeability, vasodilation, edema formation, hypotension, pain, fever (14) : all typical clinical features of COVID-19. (79) hypothesized that a kinin-dependent local lung angioedema via B1R and eventually B2R is an important feature of COVID-19 and proposed that blocking the B2R and inhibiting plasma KAL activity might be beneficial in early disease, preventing ARDS.

abstract:
  To date the pathophysiology of COVID-19 remains unclear: this represents a factor determining the current lack of effective treatments. In this paper, we hypothesized a complex host response to SARS-CoV-2, with the Contact System (CS) playing a pivotal role in innate immune response. CS is linked with different proteolytic defense systems operating in human vasculature: the Kallikrein–Kinin (KKS), the Coagulation/Fibrinolysis and the Renin–Angiotensin (RAS) Systems. We investigated the role of the mediators involved. CS consists of Factor XII (FXII) and plasma prekallikrein (complexed to high-molecular-weight kininogen-HK). Autoactivation of FXII by contact with SARS-CoV-2 could lead to activation of intrinsic coagulation, with fibrin formation (microthrombosis), and fibrinolysis, resulting in increased D-dimer levels. Activation of kallikrein by activated FXII leads to production of bradykinin (BK) from HK. BK binds to B2-receptors, mediating vascular permeability, vasodilation and edema. B1-receptors, binding the metabolite [des-Arg(9)]-BK (DABK), are up-regulated during infections and mediate lung inflammatory responses. BK could play a relevant role in COVID-19 as already described for other viral models. Angiotensin-Converting-Enzyme (ACE) 2 displays lung protective effects: it inactivates DABK and converts Angiotensin II (Ang II) into Angiotensin-(1-7) and Angiotensin I into Angiotensin-(1-9). SARS-CoV-2 binds to ACE2 for cell entry, downregulating it: an impaired DABK inactivation could lead to an enhanced activity of B1-receptors, and the accumulation of Ang II, through a negative feedback loop, may result in decreased ACE activity, with consequent increase of BK. Therapies targeting the CS, the KKS and action of BK could be effective for the treatment of COVID-19.


id: cord-325353-tx6s4ggu
title: Neonatal Immunity, Respiratory Virus Infections, and the Development of Asthma
author: Restori, Katherine H.
date: 2018-06-04
txt: ./txt/cord-325353-tx6s4ggu.txt
cache: ./cache/cord-325353-tx6s4ggu.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2018.01249
doi: 10.3389/fimmu.2018.01249
summary:
  The goals of this review are (1) to outline the differences between the neonatal and adult immune systems and (2) to present murine and human data that support the hypothesis that early-life interactions between the immune system and respiratory viruses can create a lung environment conducive to the development of asthma. Because RSV, influenza, and RVs cause a large proportion of respiratorytract infections in neonates, we will focus primarily on these three pathogens as models to better understand how early-life infection and antiviral immune responses might contribute to the subsequent development of asthma. The addition of RSV infection of airway epithelial cells with production of the type-2 innate cytokines, IL-33 (138) , TSLP (123) , and IL-25 (128) , would, therefore, be predicted to create an even more exaggerated type-2-biased microenvironment in the lung with activation of other immune cells (e.g., M2 macrophages, DCs, and/or ILC2 cells) and the development of AHR.

abstract:
  Infants are exposed to a wide range of potential pathogens in the first months of life. Although maternal antibodies acquired transplacentally protect full-term neonates from many systemic pathogens, infections at mucosal surfaces still occur with great frequency, causing significant morbidity and mortality. At least part of this elevated risk is attributable to the neonatal immune system that tends to favor T regulatory and Th2 type responses when microbes are first encountered. Early-life infection with respiratory viruses is of particular interest because such exposures can disrupt normal lung development and increase the risk of chronic respiratory conditions, such as asthma. The immunologic mechanisms that underlie neonatal host–virus interactions that contribute to the subsequent development of asthma have not yet been fully defined. The goals of this review are (1) to outline the differences between the neonatal and adult immune systems and (2) to present murine and human data that support the hypothesis that early-life interactions between the immune system and respiratory viruses can create a lung environment conducive to the development of asthma.


id: cord-328003-yovp8squ
author: Duan, Liangwei
date: 2020-10-07
txt: ./txt/cord-328003-yovp8squ.txt
cache: ./cache/cord-328003-yovp8squ.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33117378/
doi: 10.3389/fimmu.2020.576622
summary:
  Here, we provide a comprehensive overview of the wealth of research related to the SARS-CoV-2 S glycoprotein biosynthesis, structure, function, and antigenicity, aiming to provide useful insights into the design and development of the S protein-based vaccines as well as therapeutics to prevent or treat the ongoing global spread of SARS-CoV-2/COVID-19. Prefusion structures of human coronavirus HKU1 (HCoV-HKU1) and mouse hepatitis virus S protein ectodomains without two consecutive proline mutations reveal only fully closed conformation (37, 42) , similar to that observed for a full-length, wild-type prefusion form of the SARS-CoV-2 S glycoprotein (41) . Therefore, SARS-CoV-2 evades immune surveillance also through conformational masking, which is well-documented for HIV-1 (43, 44) ; while at the same time, the S protein could transiently sample the functional state to engage ACE2, consistent with the notion that the fusion glycoprotein of highly pathogenic viruses have evolved to perform its functions while evading host neutralizing antibody responses.

title:
  The SARS-CoV-2 Spike Glycoprotein Biosynthesis, Structure, Function, and Antigenicity: Implications for the Design of Spike-Based Vaccine Immunogens

abstract:
  The ongoing pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses a grave threat to global public health and imposes a severe burden on the entire human society. Like other coronaviruses, the SARS-CoV-2 genome encodes spike (S) glycoproteins, which protrude from the surface of mature virions. The S glycoprotein plays essential roles in virus attachment, fusion and entry into the host cell. Surface location of the S glycoprotein renders it a direct target for host immune responses, making it the main target of neutralizing antibodies. In the light of its crucial roles in viral infection and adaptive immunity, the S protein is the focus of most vaccine strategies as well as therapeutic interventions. In this review, we highlight and describe the recent progress that has been made in the biosynthesis, structure, function, and antigenicity of the SARS-CoV-2 S glycoprotein, aiming to provide valuable insights into the design and development of the S protein-based vaccines as well as therapeutics.


id: cord-328011-6lf3no6u
author: Zayed, Hatem
date: 2020-08-14
txt: ./txt/cord-328011-6lf3no6u.txt
cache: ./cache/cord-328011-6lf3no6u.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.02051
doi: 10.3389/fimmu.2020.02051
abstract: nan
summary:
  title: Vaccine Development Against COVID-19 Prior to Pandemic Outbreaks, Using in vitro Evolution and Reverse Genetics Since coronaviruses are increasing alarmingly, there is an urgent need for a safe and effective vaccine to prevent the spread of the virus during pandemic outbreaks, and stop deaths associated with the virulent COVID-19. We now know that SARS-CoV-2 shares 88% identity with two SARS-like coronaviruses (bat-SL-CoVZXC21 and bat-SL-CoVZC45) that both originated in China, and use the same human angiotensin-converting enzyme 2 receptor for cell entry during the process of infection (3). In response to such forewarnings from scientists, a predictive vaccine could have been designed and developed for the potential virus pandemic. Thereafter, during the time of pandemic, suitable stored transgenic cell lines could be used, based on the Abbreviations: COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; VLP, virus-like particle; WHO, World Health Organization.

title:
  Vaccine Development Against COVID-19 Prior to Pandemic Outbreaks, Using in vitro Evolution and Reverse Genetics


id: cord-328549-r56lih8j
title: Regulation of RIG-I Activation by K63-Linked Polyubiquitination
author: Okamoto, Masaaki
date: 2018-01-05
txt: ./txt/cord-328549-r56lih8j.txt
cache: ./cache/cord-328549-r56lih8j.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/29354136/
doi: 10.3389/fimmu.2017.01942
summary:
  First, it was reported that TRIM25 ubiquitin ligase delivered K63-linked polyubiquitin moiety to the 2CARDs. The polyubiquitin chain stabilizes a structure called the 2CARD tetramer, in which four 2CARDs assemble and make a core that promotes the aggregation of the mitochondrial antiviral-signaling (MAVS) protein on mitochondria. First, it was reported that TRIM25 ubiquitin ligase delivered K63-linked polyubiquitin moiety to the 2CARDs. The polyubiquitin chain stabilizes a structure called the 2CARD tetramer, in which four 2CARDs assemble and make a core that promotes the aggregation of the mitochondrial antiviral-signaling (MAVS) protein on mitochondria. However, subsequent studies have reported that Riplet, MEX3C, and TRIM4 ubiquitin ligases are also involved in K63-linked polyubiquitination and the activation of RIG-I. However, recent studies have reported three other ubiquitin ligases, RING finger protein leading to RIG-I activation (Riplet), mex-3 RNA-binding family member C (MEX3C), and TRIM4, which are required for the polyubiquitination and activation of RIG-I (28-30).

abstract:
  RIG-I is a pattern recognition receptor and recognizes cytoplasmic viral double-stranded RNA (dsRNA). Influenza A virus, hepatitis C virus, and several other pathogenic viruses are mainly recognized by RIG-I, resulting in the activation of the innate immune responses. The protein comprises N-terminal two caspase activation and recruitment domains (2CARDs), an RNA helicase domain, and the C-terminal domain (CTD). The CTD recognizes 5′-triphosphate viral dsRNA. After recognition of viral dsRNA, the protein harbors K63-linked polyubiquitination essential for RIG-I activation. First, it was reported that TRIM25 ubiquitin ligase delivered K63-linked polyubiquitin moiety to the 2CARDs. The polyubiquitin chain stabilizes a structure called the 2CARD tetramer, in which four 2CARDs assemble and make a core that promotes the aggregation of the mitochondrial antiviral-signaling (MAVS) protein on mitochondria. MAVS aggregation then triggers the signal to induce the innate immune responses. However, subsequent studies have reported that Riplet, MEX3C, and TRIM4 ubiquitin ligases are also involved in K63-linked polyubiquitination and the activation of RIG-I. MEX3C and TRIM4 mediate polyubiquitination of the 2CARDs. By contrast, Riplet ubiquitinates the CTD. The physiological significance of each ubiquitin ligases has been shown by knockout and knockdown studies, but there appears to be contradictory to evidence reported in the literature. In this review, we summarize recent findings related to K63-linked polyubiquitination and propose a model that could reconcile current contradictory theories. We also discuss the physiological significance of the ubiquitin ligases in the immune system against viral infection.


id: cord-328763-hcbs20a0
title: Potential for Targeting Myeloid Cells in Controlling CNS Inflammation
author: Ifergan, Igal
date: 2020-10-06
url: https://www.ncbi.nlm.nih.gov/pubmed/33123148/
doi: 10.3389/fimmu.2020.571897
abstract:
  Multiple Sclerosis (MS) is characterized by immune cell infiltration to the central nervous system (CNS) as well as loss of myelin. Characterization of the cells in lesions of MS patients revealed an important accumulation of myeloid cells such as macrophages and dendritic cells (DCs). Data from the experimental autoimmune encephalomyelitis (EAE) model of MS supports the importance of peripheral myeloid cells in the disease pathology. However, the majority of MS therapies focus on lymphocytes. As we will discuss in this review, multiple strategies are now in place to target myeloid cells in clinical trials. These strategies have emerged from data in both human and mouse studies. We discuss strategies targeting myeloid cell migration, growth factors and cytokines, biological functions (with a focus on miRNAs), and immunological activities (with a focus on nanoparticles).


id: cord-330417-8nnobx8g
author: Herrmann, Marissa
date: 2020-08-26
txt: ./txt/cord-330417-8nnobx8g.txt
cache: ./cache/cord-330417-8nnobx8g.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32983106/
doi: 10.3389/fimmu.2020.01870
summary:
  Following the hypothesis that T cells in COVID-19 might have a similar, dual function, we comprehensively characterized the differentiation (CCR7, CD45RO) and activation status (HLA-DR, CD38, CD69, CD226), the co-expression of co-inhibitory molecules (PD1, TIM-3, LAG-3, BTLA, TIGIT), as well as the expression pattern of the transcription factors T-bet and eomes of CD8 + and CD4 + T cells of PBMC of n = 20 SARS-CoV-2 patients compared to n = 10 P. Following the hypothesis that T cells in COVID-19 might have a similar, dual function, we comprehensively characterized the differentiation (CCR7, CD45RO) and activation status (HLA-DR, CD38, CD69, CD226), the co-expression of co-inhibitory molecules (PD1, TIM-3, LAG-3, BTLA, TIGIT), as well as the expression pattern of the transcription factors T-bet and eomes of CD8 + and CD4 + T cells of PBMC of n = 20 SARS-CoV-2 patients compared to n = 10 P.

title:
  Analysis of Co-inhibitory Receptor Expression in COVID-19 Infection Compared to Acute Plasmodium falciparum Malaria: LAG-3 and TIM-3 Correlate With T Cell Activation and Course of Disease

abstract:
  Coronavirus disease 2019 (COVID-19) which is caused by the novel SARS-CoV-2 virus is a severe flu-like illness which is associated with hyperinflammation and immune dysfunction. The virus induces a strong T and B cell response but little is known about the immune pathology of this viral infection. Acute Plasmodium falciparum malaria also causes acute clinical illness and is characterized by hyperinflammation due to the strong production of pro-inflammatory cytokines and a massive activation of T cells. In malaria, T cells express a variety of co-inhibitory receptors which might be a consequence of their activation but also might limit their overwhelming function. Thus, T cells are implicated in protection as well as in pathology. The outcome of malaria is thought to be a consequence of the balance between co-activation and co-inhibition of T cells. Following the hypothesis that T cells in COVID-19 might have a similar, dual function, we comprehensively characterized the differentiation (CCR7, CD45RO) and activation status (HLA-DR, CD38, CD69, CD226), the co-expression of co-inhibitory molecules (PD1, TIM-3, LAG-3, BTLA, TIGIT), as well as the expression pattern of the transcription factors T-bet and eomes of CD8(+) and CD4(+) T cells of PBMC of n = 20 SARS-CoV-2 patients compared to n = 10 P. falciparum infected patients and n = 13 healthy controls. Overall, acute COVID-19 and malaria infection resulted in a comparably elevated activation and altered differentiation status of the CD8(+) and CD4(+) T cell populations. T effector cells of COVID-19 and malaria patients showed higher frequencies of the inhibitory receptors T-cell immunoglobulin mucin-3 (TIM-3) and Lymphocyte-activation gene-3 (LAG-3) which was linked to increased activation levels and an upregulation of the transcription factors T-bet and eomes. COVID-19 patients with a more severe disease course showed higher levels of LAG-3 and TIM-3 than patients with a mild disease course. During recovery, a rapid normalization of these inhibitory receptors could be observed. In summary, comparing the expression of different co-inhibitory molecules in CD8(+) and CD4(+) T cells in COVID-19 vs. malaria, there is a transient increase of the expression of certain inhibitory receptors like LAG-3 and TIM-3 in COVID-19 in the overall context of acute immune activation.


id: cord-332150-j76726no
author: De Stefano, Ludovico
date: 2020-10-06
txt: ./txt/cord-332150-j76726no.txt
cache: ./cache/cord-332150-j76726no.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.572635
doi: 10.3389/fimmu.2020.572635
summary:
  The main challenge for effective administration of anti-cytokine therapy in COVID-19 will be therefore to better define a precise "window of therapeutic opportunity." Only considering a more specific set of criteria able to integrate information on direct viral damage, the cytokine burden, and the patient''s immune vulnerability, it will be possible to decide, carefully balancing both benefits and risks, the appropriateness of using immunosuppressive drugs even in patients affected primarily by an infectious disease. Discovery of virus and host genomic factors will undoubtedly support risk stratification and targeted treatment; however, as genomic studies require long times before entering clinical practice, it is urgent to integrate easily accessible information on the dynamics and pathogenicity of the immune response during the different phases of SARS-CoV-2 infection. Accordingly, longitudinal immune profiling of hospitalized COVID-19 cases with different outcomes has recently shown that, despite similar levels of inflammatory cytokines in the first 10 days from symptom onset, patients with less severe disease evolution also express mediators of wound healing and tissue repair (41) .

title:
  A “Window of Therapeutic Opportunity” for Anti-Cytokine Therapy in Patients With Coronavirus Disease 2019

abstract:
  The effects of cytokine inhibition in the different phases of the severe coronavirus disease 2019 (COVID-19) are currently at the center of intense debate, and preliminary results from observational studies and case reports offer conflicting results thus far. The identification of the correct timing of administration of anti-cytokine therapies and other immunosuppressants in COVID-19 should take into account the intricate relationship between the viral burden, the hyperactivation of the innate immune system and the adaptive immune dysfunction. The main challenge for effective administration of anti-cytokine therapy in COVID-19 will be therefore to better define a precise “window of therapeutic opportunity.” Only considering a more specific set of criteria able to integrate information on direct viral damage, the cytokine burden, and the patient’s immune vulnerability, it will be possible to decide, carefully balancing both benefits and risks, the appropriateness of using immunosuppressive drugs even in patients affected primarily by an infectious disease.


id: cord-333041-69n2wwn3
author: Pal, Anandita
date: 2020-08-11
txt: ./txt/cord-333041-69n2wwn3.txt
cache: ./cache/cord-333041-69n2wwn3.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.01997
doi: 10.3389/fimmu.2020.01997
summary:
  Obesity is a major independent risk factor for increased morbidity and mortality upon infection with Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), which is responsible for the current coronavirus disease pandemic (COVID-19). We further discuss how the effects of obesity upon SARS-CoV-2 infection are likely exacerbated with environmental exposures that promote chronic pulmonary inflammation and augment SPM deficits. Obesity is an independent risk factor for increased morbidity and mortality upon infection with the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) responsible for the current COVID-19 pandemic. The SPM precursor 17-hydroxydocosahexaenoic acid (17-HDHA) increased antibody levels and improved survival upon pH1N1 influenza vaccination and infection in lean mice by promoting B cell differentiation toward the formation of CD138 + long-lived antibody secreting cells (18) . Taken together, these data suggest that the susceptibility of obese individuals to environmental lung diseases may drive an altered pulmonary immune response and a state of SPM deficiency that increases the morbidity and mortality to respiratory infections, including COVID-19.

title:
  Obesity-Driven Deficiencies of Specialized Pro-resolving Mediators May Drive Adverse Outcomes During SARS-CoV-2 Infection

abstract:
  Obesity is a major independent risk factor for increased morbidity and mortality upon infection with Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), which is responsible for the current coronavirus disease pandemic (COVID-19). Therefore, there is a critical need to identify underlying metabolic factors associated with obesity that could be contributing toward increased susceptibility to SARS-CoV-2 in this vulnerable population. Here, we focus on the critical role of potent endogenous lipid metabolites known as specialized pro-resolving mediators (SPMs) that are synthesized from polyunsaturated fatty acids. SPMs are generated during the transition of inflammation to resolution and have a vital role in directing damaged tissues to homeostasis; furthermore, SPMs display anti-viral activity in the context of influenza infection without being immunosuppressive. We cover evidence from rodent and human studies to show that obesity, and its co-morbidities, induce a signature of SPM deficiency across immunometabolic tissues. We further discuss how the effects of obesity upon SARS-CoV-2 infection are likely exacerbated with environmental exposures that promote chronic pulmonary inflammation and augment SPM deficits. Finally, we highlight potential approaches to overcome the loss of SPMs using dietary and pharmacological interventions. Collectively, this mini-review underscores the need for mechanistic studies on how SPM deficiencies driven by obesity and environmental exposures may exacerbate the response to SARS-CoV-2.


id: cord-333670-qv1orlv5
title: Coronavirus Disease (Covid-19): What Are We Learning in a Country With High Mortality Rate?
author: Mutti, Luciano
date: 2020-05-28
txt: ./txt/cord-333670-qv1orlv5.txt
cache: ./cache/cord-333670-qv1orlv5.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32574270/
doi: 10.3389/fimmu.2020.01208
abstract: nan
summary:
  In Italy, the possibility of performing autopsies or post-mortem diagnostic studies on suspect, probable, or confirmed COVID-19 cases has been intensively debated (5, 6) ; however, postmortem pathological analysis of COVID-19 patients in China has shown findings consistent with Acute Respiratory Distress Syndrome (ARDS) (7-9) (Figure 1 ). Consistently, recent results indicate that a systemic immune dysregulation that triggers auto-sustaining inflammatory lung damage, causing fatal respiratory-failure and consequent multiorgan-failure, is the main virus-related-death cause in patients who develop SARS-CoV-2 (10). Overall, understanding the role of pro-inflammatory cytokines certainly unravels a new battleground against the lethal clinical effect of CODIV-19 infection; this, along with the identification of a high-risk autoimmune profile, including the genotyping of Class I and II HLA, which have a key role in shaping the anti-viral immune response and Th1/Th2 lymphocyte subset response (Figure 1) , and immune-profiling, could also help to prevent these dangerous evolutions of the disease (29) .


id: cord-333932-aqcllik0
title: Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19)
author: Diao, Bo
date: 2020-05-01
txt: ./txt/cord-333932-aqcllik0.txt
cache: ./cache/cord-333932-aqcllik0.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32425950/
doi: 10.3389/fimmu.2020.00827
summary:
  Methods: We retrospectively reviewed the counts of T cells and serum cytokine concentration from data of 522 patients with laboratory-confirmed COVID-19 and 40 healthy controls. Our results thus provide a preliminary demonstration of T cell exhaustion during COVID-19 infection and suggest that more urgent, early intervention may be required in patients with low T lymphocyte counts. The expression of angiotensin converting enzyme 2 (ACE2), the predicted receptor of SARS-CoV-2 viruses, is absent on T cells (11) , suggesting that the depressed T counts in COVID-19 patients mentioned above (Figure 1 ) were likely not caused by direct infection of T cells. We demonstrate here that COVID-19 patients have very high levels of serum IL-10 following SARS-CoV-2 infection, while also displaying high levels of the PD-1 and Tim-3 exhaustion markers on their T cells, suggesting that IL-10 might be mechanistically responsible.

abstract:
  Background: The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed great threat to human health. T cells play a critical role in antiviral immunity but their numbers and functional state in COVID-19 patients remain largely unclear. Methods: We retrospectively reviewed the counts of T cells and serum cytokine concentration from data of 522 patients with laboratory-confirmed COVID-19 and 40 healthy controls. In addition, the expression of T cell exhaustion markers were measured in 14 COVID-19 cases. Results: The number of total T cells, CD4(+) and CD8(+) T cells were dramatically reduced in COVID-19 patients, especially in patients requiring Intensive Care Unit (ICU) care. Counts of total T cells, CD8(+) T cells or CD4(+) T cells lower than 800, 300, or 400/μL, respectively, were negatively correlated with patient survival. T cell numbers were negatively correlated to serum IL-6, IL-10, and TNF-α concentration, with patients in the disease resolution period showing reduced IL-6, IL-10, and TNF-α concentrations and restored T cell counts. T cells from COVID-19 patients had significantly higher levels of the exhausted marker PD-1. Increasing PD-1 and Tim-3 expression on T cells was seen as patients progressed from prodromal to overtly symptomatic stages. Conclusions: T cell counts are reduced significantly in COVID-19 patients, and the surviving T cells appear functionally exhausted. Non-ICU patients with total T cells counts lower than 800/μL may still require urgent intervention, even in the immediate absence of more severe symptoms due to a high risk for further deterioration in condition.


id: cord-334564-bqh9jkds
title: Psycho-Neuroendocrine-Immune Interactions in COVID-19: Potential Impacts on Mental Health
author: Raony, Ícaro
date: 2020-05-27
txt: ./txt/cord-334564-bqh9jkds.txt
cache: ./cache/cord-334564-bqh9jkds.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.01170
doi: 10.3389/fimmu.2020.01170
summary:
  Since COVID-19 is associated with increased levels of pro-inflammatory cytokines (8) , an immune signature shared with several psychiatric disorders, we propose how the relationship between SARS-CoV-2/host can possibly impair interactions between the immune, nervous and endocrine systems, leading to psychiatric symptoms. Several studies have demonstrated psychiatric manifestations in patients with MERS or SARS during the acute phase, such as increased stress levels, impaired memory, symptoms of depression, anxiety, PTSD, psychoses, and suicidal behavior (28) (29) (30) (31) (32) (33) . If the increase in cytokine levels and the manifestation of psychiatric symptoms are related to the severity of the symptoms of SARS-CoV infection, the "cytokine storm" might also be related to the "mental health thunderstorms" seen in patients with COVID-19? Similar to possible mechanisms involved in the impacts of SARS-CoV-2 infection on mental health, social isolation may also be associated with dysfunctional psycho-neuroendocrine-immune interactions, which in turn can contribute to the development or the worsening of psychiatric disturbances (Figure 2) .

abstract:
  Coronavirus disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The impacts of the disease may be beyond the respiratory system, also affecting mental health. Several factors may be involved in the association between COVID-19 and psychiatric outcomes, such as fear inherent in the pandemic, adverse effects of treatments, as well as financial stress, and social isolation. Herein we discuss the growing evidence suggesting that the relationship between SARS-CoV-2 and host may also trigger changes in brain and behavior. Based on the similarity of SARS-CoV-2 with other coronaviruses, it is conceivable that changes in endocrine and immune response in the periphery or in the central nervous system may be involved in the association between SARS-CoV-2 infection and impaired mental health. This is likely to be further enhanced, since millions of people worldwide are isolated in quarantine to minimize the transmission of SARS-CoV-2 and social isolation can also lead to neuroendocrine-immune changes. Accordingly, we highlight here the hypothesis that neuroendocrine-immune interactions may be involved in negative impacts of SARS-CoV-2 infection and social isolation on psychiatric issues.


id: cord-336201-fl606l3b
title: The Effects of Type 2 Diabetes Mellitus on Organ Metabolism and the Immune System
author: Daryabor, Gholamreza
date: 2020-07-22
txt: ./txt/cord-336201-fl606l3b.txt
cache: ./cache/cord-336201-fl606l3b.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32793223/
doi: 10.3389/fimmu.2020.01582
summary:
  Obesity-related immune cell infiltration, inflammation, and increased oxidative stress promote metabolic impairments in the insulin-sensitive tissues and finally, insulin resistance, organ failure, and premature aging occur. T2DM, the most common form of diabetes (∼90%), is characterized by a systemic inflammatory disease accompanied by insulin resistance (IR) or decreased metabolic response to insulin in several tissues, including the adipose tissue, liver, and skeletal muscle, as well as by reduced insulin synthesis by pancreatic beta cells (4, 5) . During the progression of diabetes, hyperglycemia promotes mitochondrial dysfunction and induces the formation of reactive oxygen species (ROS) that cause oxidative stress in several tissues such as blood vessels and pancreatic beta cells (7) (8) (9) . In addition, the attachment of AGEs to their receptors [e.g., CD36, galectin-3, scavenger receptors types I (SR-A1), and II (SR-A2)] on the surfaces of immune cells in the circulation and tissues activates the expression of pro-inflammatory cytokines and increases free radical generation (18) .

abstract:
  Metabolic abnormalities such as dyslipidemia, hyperinsulinemia, or insulin resistance and obesity play key roles in the induction and progression of type 2 diabetes mellitus (T2DM). The field of immunometabolism implies a bidirectional link between the immune system and metabolism, in which inflammation plays an essential role in the promotion of metabolic abnormalities (e.g., obesity and T2DM), and metabolic factors, in turn, regulate immune cell functions. Obesity as the main inducer of a systemic low-level inflammation is a main susceptibility factor for T2DM. Obesity-related immune cell infiltration, inflammation, and increased oxidative stress promote metabolic impairments in the insulin-sensitive tissues and finally, insulin resistance, organ failure, and premature aging occur. Hyperglycemia and the subsequent inflammation are the main causes of micro- and macroangiopathies in the circulatory system. They also promote the gut microbiota dysbiosis, increased intestinal permeability, and fatty liver disease. The impaired immune system together with metabolic imbalance also increases the susceptibility of patients to several pathogenic agents such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thus, the need for a proper immunization protocol among such patients is granted. The focus of the current review is to explore metabolic and immunological abnormalities affecting several organs of T2DM patients and explain the mechanisms, whereby diabetic patients become more susceptible to infectious diseases.


id: cord-336924-7xcbtn3q
author: Borghi, Maria Orietta
date: 2020-10-15
txt: ./txt/cord-336924-7xcbtn3q.txt
cache: ./cache/cord-336924-7xcbtn3q.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.584241
doi: 10.3389/fimmu.2020.584241
summary:
  OBJECTIVE: To evaluate the prevalence and the clinical association of aPL in a large cohort of COVID-19 patients, and to characterize the epitope specificity of anti-β(2)GPI antibodies. aPL in COVID-19 patients are mainly directed against β(2)GPI but display an epitope specificity different from antibodies in antiphospholipid syndrome. The prevalence of COVID-19 patients positive for aCL and anti-b 2 GPI IgG/IgA/ IgM detected by ELISA and CIA is summarized in Table 2 . Again, there was no association between prolonged aPTT and the presence of aPS/PT antibodies nor with thrombotic events in our COVID-19 cohort. Again, there was no association between prolonged aPTT and the presence of aPS/PT antibodies nor with thrombotic events in our COVID-19 cohort. In conclusion, while the medium/high aPL titers with D1 specificity are associated with vascular events in APS, low antibody titers with reactivity against b 2 GPI epitope(s) different from D1 or D4,5 can be found in COVID-19.

title:
  Anti-Phospholipid Antibodies in COVID-19 Are Different From Those Detectable in the Anti-Phospholipid Syndrome

abstract:
  BACKGROUND: Critically ill patients with coronavirus disease 2019 (COVID-19) have a profound hypercoagulable state and often develop coagulopathy which leads to organ failure and death. Because of a prolonged activated partial-thromboplastin time (aPTT), a relationship with anti-phospholipid antibodies (aPLs) has been proposed, but results are controversial. Functional assays for aPL (i.e., lupus anticoagulant) can be influenced by concomitant anticoagulation and/or high levels of C reactive protein. The presence of anti-cardiolipin (aCL), anti-beta2-glycoprotein I (anti-β(2)GPI), and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies was not investigated systematically. Epitope specificity of anti-β(2)GPI antibodies was not reported. OBJECTIVE: To evaluate the prevalence and the clinical association of aPL in a large cohort of COVID-19 patients, and to characterize the epitope specificity of anti-β(2)GPI antibodies. METHODS: ELISA and chemiluminescence assays were used to test 122 sera of patients suffering from severe COVID-19. Of them, 16 displayed major thrombotic events. RESULTS: Anti-β(2)GPI IgG/IgA/IgM was the most frequent in 15.6/6.6/9.0% of patients, while aCL IgG/IgM was detected in 5.7/6.6% by ELISA. Comparable values were found by chemiluminescence. aPS/PT IgG/IgM were detectable in 2.5 and 9.8% by ELISA. No association between thrombosis and aPL was found. Reactivity against domain 1 and 4-5 of β(2)GPI was limited to 3/58 (5.2%) tested sera for each domain and did not correlate with aCL/anti-β(2)GPI nor with thrombosis. CONCLUSIONS: aPL show a low prevalence in COVID-19 patients and are not associated with major thrombotic events. aPL in COVID-19 patients are mainly directed against β(2)GPI but display an epitope specificity different from antibodies in antiphospholipid syndrome.


id: cord-338092-barmkkwx
title: Immunity to Pathogens Taught by Specialized Human Dendritic Cell Subsets
author: Geginat, Jens
date: 2015-10-13
txt: ./txt/cord-338092-barmkkwx.txt
cache: ./cache/cord-338092-barmkkwx.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2015.00527
doi: 10.3389/fimmu.2015.00527
summary:
  Upon viral infections, plasmacytoid DCs (pDCs) rapidly produce large amounts of IFN-α, which has potent antiviral functions and activates several other immune cells. BDCA-3(+) mDC2 are the human homologue of CD8α(+) mDCs, since they share the expression of several key molecules, the capacity to cross-present antigens to CD8(+) T-cells and to produce IFN-λ. Dendritic cells (DCs) can express very high levels of MHC and costimulatory molecules, and it is generally accepted that they are the relevant cells to induce the activation ("priming") of antigen-specific "naive" T cells (1, 2) and induce their differentiation into various types of effector T cells. Overall, these differences in pathogen sensing and T-cell activation between human and murine DCs are likely to have an important impact on their role in immune responses against specific pathogens. Dendritic cell subsets in humans and mice express not only different patterns of toll-like receptors, but they have also partially distinct cytokine profiles (Figure 1) .

abstract:
  Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) that have a key role in immune responses because they bridge the innate and adaptive arms of the immune system. They mature upon recognition of pathogens and upregulate MHC molecules and costimulatory receptors to activate antigen-specific CD4(+) and CD8(+) T cells. It is now well established that DCs are not a homogeneous population but are composed of different subsets with specialized functions in immune responses to specific pathogens. Upon viral infections, plasmacytoid DCs (pDCs) rapidly produce large amounts of IFN-α, which has potent antiviral functions and activates several other immune cells. However, pDCs are not particularly potent APCs and induce the tolerogenic cytokine IL-10 in CD4(+) T cells. In contrast, myeloid DCs (mDCs) are very potent APCs and possess the unique capacity to prime naive T cells and consequently to initiate a primary adaptive immune response. Different subsets of mDCs with specialized functions have been identified. In mice, CD8α(+) mDCs capture antigenic material from necrotic cells, secrete high levels of IL-12, and prime Th1 and cytotoxic T-cell responses to control intracellular pathogens. Conversely, CD8α(−) mDCs preferentially prime CD4(+) T cells and promote Th2 or Th17 differentiation. BDCA-3(+) mDC2 are the human homologue of CD8α(+) mDCs, since they share the expression of several key molecules, the capacity to cross-present antigens to CD8(+) T-cells and to produce IFN-λ. However, although several features of the DC network are conserved between humans and mice, the expression of several toll-like receptors as well as the production of cytokines that regulate T-cell differentiation are different. Intriguingly, recent data suggest specific roles for human DC subsets in immune responses against individual pathogens. The biology of human DC subsets holds the promise to be exploitable in translational medicine, in particular for the development of vaccines against persistent infections or cancer.


id: cord-338261-tyimwctm
title: Role of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair
author: Farr, Laura
date: 2020-06-23
txt: ./txt/cord-338261-tyimwctm.txt
cache: ./cache/cord-338261-tyimwctm.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32655566/
doi: 10.3389/fimmu.2020.01273
summary:
  title: Role of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair This mini review focuses on emerging literature on the role of the cytokine macrophage migration inhibitory factor (MIF) and its cell membrane receptor CD74, in protecting against injury and promoting healing in different parts of the body. This review focuses on the recent advances that have greatly contributed to our current understanding of the link between the signaling pathways activated upon binding of macrophage migration inhibitory factor cytokine to its membrane receptor CD74 and wound healing in different body parts (Figure 1 ). The complex pathological processes that result in disease combined with CD74''s expression on a variety of cell types, and its multiple co-receptors with diverse downstream signaling pathways contribute to these varied outcomes. Surface expression of CD74 by type II alveolar epithelial cells: a potential mechanism for macrophage migration inhibitory factor-induced epithelial repair

abstract:
  Wound healing after an injury is essential for life. An in-depth understanding of the healing process is necessary to ultimately improve the currently limited treatment options for patients suffering as a result of damage to various organs and tissues. Injuries, even the most minor, trigger an inflammatory response that protects the host and activates repair pathways. In recent years, substantial progress has been made in delineating the mechanisms by which inflammatory cytokines and their receptors facilitate tissue repair and regeneration. This mini review focuses on emerging literature on the role of the cytokine macrophage migration inhibitory factor (MIF) and its cell membrane receptor CD74, in protecting against injury and promoting healing in different parts of the body.


id: cord-338498-3238fz73
author: Kleen, Thomas-Oliver
date: 2020-09-04
txt: ./txt/cord-338498-3238fz73.txt
cache: ./cache/cord-338498-3238fz73.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.02059
doi: 10.3389/fimmu.2020.02059
summary:
  Bacterial "new old friends" such as Bacille Calmette-Guérin (BCG) or Mycobacterium obuense have the ability to elevate basal systemic levels of type 1 cytokines and immune cells, correlating with increased protection against diverse and unrelated infectious agents, called "trained immunity." Here we describe dysfunctional immune responses induced by coronaviruses, representing potentially difficult to overcome obstacles to safe, effective vaccine development for COVID-19, and outline how trained immunity could help protect high risk populations through immunomodulation with BCG and other "new old friends." One recent example of the need for continued vigilance is a study using Chinese macaques indicating cause for concern by showing that vaccine-induced, S-specific immunity in the form of anti-spike IgG resulted in severe ALI by skewing macrophage responses during subsequent, acute infection with closely related SARS-CoV (139) .

title:
  Mitigating Coronavirus Induced Dysfunctional Immunity for At-Risk Populations in COVID-19: Trained Immunity, BCG and “New Old Friends”

abstract:
  The novel, highly contagious coronavirus SARS-CoV-2 spreads rapidly throughout the world, leading to a deadly pandemic of a predominantly respiratory illness called COVID-19. Safe and effective anti-SARS-CoV-2 vaccines are urgently needed. However, emerging immunological observations show hallmarks of significant immunopathological characteristics and dysfunctional immune responses in patients with COVID-19. Combined with existing knowledge about immune responses to other closely related and highly pathogenic coronaviruses, this could forebode significant challenges for vaccine development, including the risk of vaccine failure. Animal data from earlier coronavirus vaccine efforts indicate that elderly people, most at risk from severe COVID-19 disease, could be especially at risk from immunopathologic responses to novel coronavirus vaccines. Bacterial “new old friends” such as Bacille Calmette-Guérin (BCG) or Mycobacterium obuense have the ability to elevate basal systemic levels of type 1 cytokines and immune cells, correlating with increased protection against diverse and unrelated infectious agents, called “trained immunity.” Here we describe dysfunctional immune responses induced by coronaviruses, representing potentially difficult to overcome obstacles to safe, effective vaccine development for COVID-19, and outline how trained immunity could help protect high risk populations through immunomodulation with BCG and other “new old friends.”


id: cord-339152-wfakzb6w
title: Viral Emerging Diseases: Challenges in Developing Vaccination Strategies
author: Trovato, Maria
date: 2020-09-03
txt: ./txt/cord-339152-wfakzb6w.txt
cache: ./cache/cord-339152-wfakzb6w.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33013898/
doi: 10.3389/fimmu.2020.02130
summary:
  Ebola and Marburg hemorrhagic fevers, Lassa fever, Dengue fever, Yellow fever, West Nile fever, Zika, and Chikungunya vector-borne diseases, Swine flu, Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the recent Coronavirus disease 2019 (COVID-19) are examples of zoonoses that have spread throughout the globe with such a significant impact on public health that the scientific community has been called for a rapid intervention in preventing and treating emerging infections. The occurrence of significant disease outbreaks-such as SARS (severe acute respiratory syndrome) originating in China in 2002 (8) , the 2009 H1N1 swine flu pandemic from Mexico (9) , MERS (Middle East respiratory syndrome) that occurred in Saudi Arabia in 2012 (10) , the West African outbreak of Ebola virus (EBOV) in late 2013 (11) , the Zika virus (ZIKV) outbreak originating in Brazil in 2015 (12) , the 2018 health emergence in Nigeria caused by Lassa virus (13) , and the ongoing Coronavirus disease 2019 (COVID19) pandemic (14) -has renewed interests in developing strategies to faster prevent, treat, and/or control emerging and re-emerging viruses with high epidemic potential.

abstract:
  In the last decades, a number of infectious viruses have emerged from wildlife or re-emerged, generating serious threats to the global health and to the economy worldwide. Ebola and Marburg hemorrhagic fevers, Lassa fever, Dengue fever, Yellow fever, West Nile fever, Zika, and Chikungunya vector-borne diseases, Swine flu, Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the recent Coronavirus disease 2019 (COVID-19) are examples of zoonoses that have spread throughout the globe with such a significant impact on public health that the scientific community has been called for a rapid intervention in preventing and treating emerging infections. Vaccination is probably the most effective tool in helping the immune system to activate protective responses against pathogens, reducing morbidity and mortality, as proven by historical records. Under health emergency conditions, new and alternative approaches in vaccine design and development are imperative for a rapid and massive vaccination coverage, to manage a disease outbreak and curtail the epidemic spread. This review gives an update on the current vaccination strategies for some of the emerging/re-emerging viruses, and discusses challenges and hurdles to overcome for developing efficacious vaccines against future pathogens.


id: cord-340228-mvqoyror
author: Al-Herz, Waleed
date: 2019-05-29
txt: ./txt/cord-340228-mvqoyror.txt
cache: ./cache/cord-340228-mvqoyror.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/31191561/
doi: 10.3389/fimmu.2019.01231
summary:
  Results: A total of 274 PID children were registered in KNPIDR during the study period with predominance of immunodeficiencies affecting cellular and humoral immunity, followed by combined immunodeficiencies with associated syndromic features and diseases of immune dysregulation. CMV and parainfluenza infections were more common in the group of immunodeficiencies affecting cellular and humoral immunity while EBV and human papilloma virus (HPV) were more common in the immune dysregulation group and combined immunodeficiencies with associated syndromic features, respectively. The distribution of these patients according to PID categories is: immunodeficiencies affecting cellular and humoral immunity, 97 patients (35.4%); combined immunodeficiencies with associated syndromic features, 67 patients (24.5%); predominantly antibody deficiencies, 34 patients (12.4%); diseases of immune dysregulation, 47 patients (17.2%); congenital defects of phagocyte number or function, 17 patients (6.2%); autoinflammatory disorders, 1 patient (0.3%); and complement deficiencies, 11 patients (4%).

title:
  Spectrum of Viral Infections Among Primary Immunodeficient Children: Report From a National Registry

abstract:
  Objective: To present the frequency and spectrum of viral infections in primary immunodeficient children. Methods: The data was obtained from the Kuwait National Primary Immunodeficiency Disorders (PIDs) Registry during the period of 2004-2018. Results: A total of 274 PID children were registered in KNPIDR during the study period with predominance of immunodeficiencies affecting cellular and humoral immunity, followed by combined immunodeficiencies with associated syndromic features and diseases of immune dysregulation. Overall infectious complications affected 82.4% of the patients, and viral infections affected 31.7% of the registered patients. Forty-five patients (16.4%) developed viral infections caused by at least 2 organisms, among those 20 patients were affected by three or more viral infections. There was a statistically significant association between viral infections and PID category. However, there was no statistically significant association between viral infections and gender or the patients' onset age. There was a total of 170 viral infections during the study period and the causes of these infections were predominated by CMV (22.2%), adenovirus (11.7%), EBV (11.1%), and enteroviruses (7.4%). CMV and parainfluenza infections were more common in the group of immunodeficiencies affecting cellular and humoral immunity while EBV and human papilloma virus (HPV) were more common in the immune dysregulation group and combined immunodeficiencies with associated syndromic features, respectively. The most common presentation was viremia (28.8%) followed by pneumonia (28.2%) and skin infections (17.6%). The most common causes of viremia were CMV followed by adenovirus and EBV, while the most common organisms causing pneumonia were CMV followed by rhinovirus and parainfluenza. There were 80 deaths among the registered patients, 10% were caused by viral infections. Conclusions: Viral infections are common in PIDs and result into a wide-range of clinical manifestations causing significant morbidity and mortality.


id: cord-340475-h0q1m3ed
title: Type I Interferon Regulates the Expression of Long Non-Coding RNAs
author: Carnero, Elena
date: 2014-11-06
txt: ./txt/cord-340475-h0q1m3ed.txt
cache: ./cache/cord-340475-h0q1m3ed.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/25414701/
doi: 10.3389/fimmu.2014.00548
summary:
  Further validation showed that ISR2, 8, and 12 expression mimics that of their neighboring genes GBP1, IRF1, and IL6, respectively, all related to the IFN response.These genes are induced in response to different doses of IFNα2 in different cell lines at early (ISR2 or 8) or later (ISR12) time points. HuH7 cells were treated for 6, 24, 48, or 72 h with increasing doses of IFNα2 up to 10,000 units/ml, and the expression levels of GBP1, IRF1, BST2, OAS, IL6, and ISG15 were evaluated by qRT-PCR (Figure 1) .

abstract:
  Interferons (IFNs) are key players in the antiviral response. IFN sensing by the cell activates transcription of IFN-stimulated genes (ISGs) able to induce an antiviral state by affecting viral replication and release. IFN also induces the expression of ISGs that function as negative regulators to limit the strength and duration of IFN response. The ISGs identified so far belong to coding genes. However, only a small proportion of the transcriptome corresponds to coding transcripts and it has been estimated that there could be as many coding as long non-coding RNAs (lncRNAs). To address whether IFN can also regulate the expression of lncRNAs, we analyzed the transcriptome of HuH7 cells treated or not with IFNα2 by expression arrays. Analysis of the arrays showed increased levels of several well-characterized coding genes that respond to IFN both at early or late times. Furthermore, we identified several IFN-stimulated or -downregulated lncRNAs (ISRs and IDRs). Further validation showed that ISR2, 8, and 12 expression mimics that of their neighboring genes GBP1, IRF1, and IL6, respectively, all related to the IFN response. These genes are induced in response to different doses of IFNα2 in different cell lines at early (ISR2 or 8) or later (ISR12) time points. IFNβ also induced the expression of these lncRNAs. ISR2 and 8 were also induced by an influenza virus unable to block the IFN response but not by other wild-type lytic viruses tested. Surprisingly, both ISR2 and 8 were significantly upregulated in cultured cells and livers from patients infected with HCV. Increased levels of ISR2 were also detected in patients chronically infected with HIV. This is relevant as genome-wide guilt-by-association studies predict that ISR2, 8, and 12 may function in viral processes, in the IFN pathway and the antiviral response. Therefore, we propose that these lncRNAs could be induced by IFN to function as positive or negative regulators of the antiviral response.


id: cord-340741-bhxm4zua
author: Nayak, Tapas Kumar
date: 2019-04-12
txt: ./txt/cord-340741-bhxm4zua.txt
cache: ./cache/cord-340741-bhxm4zua.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2019.00786
doi: 10.3389/fimmu.2019.00786
summary:
  title: P38 and JNK Mitogen-Activated Protein Kinases Interact With Chikungunya Virus Non-structural Protein-2 and Regulate TNF Induction During Viral Infection in Macrophages Additionally, it was noticed that the expressions of key transcription factors involved mainly in antiviral responses (p-IRF3) and TNF production (p-c-jun) were induced significantly in the CHIKV infected macrophages as compared to the corresponding mock cells. In summary, for the first time it has been shown that CHIKV triggers robust TNF production in the host macrophages via both p-p38 and p-JNK/p-c-jun pathways and the interaction of viral protein, nsP2 with these MAPKs during infection. In summary, for the first time it has been shown that CHIKV triggers robust TNF production (a key mediator of CHIKV induced inflammation) in the host macrophages via both p-p38 and p-JNK/p-c-jun pathways and viral protein nsP2 interacts with both the MAPKs during infection.

title:
  P38 and JNK Mitogen-Activated Protein Kinases Interact With Chikungunya Virus Non-structural Protein-2 and Regulate TNF Induction During Viral Infection in Macrophages

abstract:
  Chikungunya virus (CHIKV), a mosquito-borne Alphavirus, is endemic in different parts of the globe. The host macrophages are identified as the major cellular reservoirs of CHIKV during infection and this virus triggers robust TNF production in the host macrophages, which might be a key mediator of virus induced inflammation. However, the molecular mechanism underneath TNF induction is not understood yet. Accordingly, the Raw264.7 cells, a mouse macrophage cell line, were infected with CHIKV to address the above-mentioned question. It was observed that CHIKV induces both p38 and JNK phosphorylation in macrophages in a time-dependent manner and p-p38 inhibitor, SB203580 is effective in reducing infection even at lower concentration as compared to the p-JNK inhibitor, SP600125. However, inhibition of p-p38 and p-JNK decreased CHIKV induced TNF production in the host macrophages. Moreover, CHIKV induced macrophage derived TNF was found to facilitate TCR driven T cell activation. Additionally, it was noticed that the expressions of key transcription factors involved mainly in antiviral responses (p-IRF3) and TNF production (p-c-jun) were induced significantly in the CHIKV infected macrophages as compared to the corresponding mock cells. Further, it was demonstrated that CHIKV mediated TNF production in the macrophages is dependent on p38 and JNK MAPK pathways linking p-c-jun transcription factor. Interestingly, it was found that CHIKV nsP2 interacts with both p-p38 and p-JNK MAPKs in the macrophages. This observation was supported by the in silico protein-protein docking analysis which illustrates the specific amino acids responsible for the nsP2-MAPKs interactions. A strong polar interaction was predicted between Thr-180 (within the phosphorylation lip) of p38 and Gln-273 of nsP2, whereas, no such polar interaction was predicted for the phosphorylation lip of JNK which indicates the differential roles of p-p38 and p-JNK during CHIKV infection in the host macrophages. In summary, for the first time it has been shown that CHIKV triggers robust TNF production in the host macrophages via both p-p38 and p-JNK/p-c-jun pathways and the interaction of viral protein, nsP2 with these MAPKs during infection. Hence, this information might shed light in rationale-based drug designing strategies toward a possible control measure of CHIKV infection in future.


