# ent

id: cord-002823-n55xvwkf
type: PROTEIN
entity:
  interferon regulatory factor 3 IRF3 IRF7 interferon gamma IFNG interferon alpha beta receptor IFNAR TIR domain


id: cord-002823-n55xvwkf
type: ORG
entity:
  Laboratory Animals National Research Council US Committee for the Update of the Guide for the Care and Use of Laboratory Animals


id: cord-000434-ff2zadol
type: DISEASE
entity:
  influenza type B virus the reactivity of anti P5 sera with two representative influenza type B virus strains B hubeiwujiagang 158 2009 Yamagata lineage


id: cord-000434-ff2zadol
type: DISEASE
entity:
  influenza A H1N1 pandemic what have we learned in the past 6 months Fields Virology Orthomyxoviridae 5th edn Characterization of a novel influenza A virus hemagglutinin


id: cord-002407-25cawzi0
type: ORG
entity:
  the National Institute of Allergy and Infectious Diseases NIAID Centers of Excellence for Influenza Research


id: cord-002407-25cawzi0
type: DISEASE
entity:
  influenza and respiratory syncytial virus in the united states Clinical and genetic characterization of severe influenza B


id: cord-002407-25cawzi0
type: DISEASE
entity:
  influenza A virus Influenza virus assembly and budding Selective packaging of the influenza A genome


id: cord-002407-25cawzi0
type: DISEASE
entity:
  influenza B viruses Influenza drug resistance Assessment of pandemic and seasonal influenza A H1N1 virus


id: cord-000354-05lnj3w0
type: PROTEIN
entity:
  Spe4262 5 9GCCTTTCTTTATGTTTTTGGCACTAGTCATTTTACCG ATGTCACTCAG Spe4263 59 CTGAGTGACATCGGTAA AATGACTAGTGCCAAAAACATAAAGAAAGGC


id: cord-000354-05lnj3w0
type: GGP
entity:
  cytochalasin D cytochalasin B Blebbistatin 17 AA geldanamycin ML 7 ML 9 PP 2 5 N ethyl N isopropyl amiloride EIPA IPA 3


id: cord-102471-dtukacm7
type: ORG
entity:
  Sequencing Provides Data for Stratifying Infection Prevention and Control Management of Nosocomial Influenza


id: cord-003169-bdw5ke4i
type: ORG
entity:
  fowl plague virus Mutation of the Second Sialic Acid Binding Site Resulting in Reduced Neuraminidase Activity


id: cord-003169-bdw5ke4i
type: DISEASE
entity:
  influenza A H3N2 viruses from 1968 to 2009 and its correspondence to haemagglutinin evolution Single hemagglutinin mutations


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-003639-bjtxf1y8
type: DISEASE
entity:
  influenza A H5N1 virus between ferrets A DNA transfection system for generation of influenza A virus from eight plasmids Purification and properties of a D galactose N acetyl D galactosamine


id: cord-255980-u0c6pg8n
type: CELL_LINE
entity:
  MDCK Dog kidney A549 Human lung CHO K1 Chinese hamster ovary Vero African green monkey kidney and 293T Human kidney cells


id: cord-011438-imbpgsub
type: PROTEIN
entity:
  polymerase basic 1 PB1 PB1 N40 PB1 F2 PB2 polymerase acid PA hemagglutinin HA nucleoprotein NP neuraminidase NA matrix 1 M1 matrix 2 M2 nonstructural protein 1 NS1


id: cord-011438-imbpgsub
type: ORG
entity:
  T Cell Immunity and Confers Protection Against Homologous and Heterologous Influenza A Virus Infections Influenza


id: cord-278465-tjjkz16y
type: WORK_OF_ART
entity:
  A Language and Environment for Statistical Computing R Foundtation for Statistical Computing Genetic


id: cord-278465-tjjkz16y
type: DISEASE
entity:
  zoonotic Woolhouse and Gowtage Sequeria 2005 and it is in environments where humans are in close proximity


id: cord-286741-h3oix9zc
type: DISEASE
entity:
  influenza A H5N1 virus between ferrets Domestic pigs have low susceptibility to H5N1 highly pathogenic avian influenza viruses Human infection


id: cord-013174-whg64w0w
type: DNA
entity:
  H3N2 human like swIAV 24 In addition to the subtypes mentioned above introductions of human seasonal IAV


id: cord-013174-whg64w0w
type: PROTEIN
entity:
  Pasteurella multocida Mycoplasma hyopneumoniae Haemophilus parasuis Actinobacillus pleuropneumoniae porcine circovirus type 2


id: cord-006362-7d5wzb7p
type: ORG
entity:
  Fetomaternal Cross Talk and Its Effect on Pregnancy Maintenance Maternal and Offspring Health Guest Editor


id: cord-291534-c6cjxq07
type: DISEASE
entity:
  influenza A virus and surfactant protein D Mechanism of adenovirus neutralization by human alpha defensins Epithelial defensins impair adenoviral infection


id: cord-291534-c6cjxq07
type: DISEASE
entity:
  respiratory syncytial virus infected human alveolar macrophages Antiviral activity of human beta defensin 3


id: cord-291014-cfnoxhtd
type: PROTEIN
entity:
  CD82 T cell immunodominance Virus like particle vaccine primes immune responses preventing inactivated virus vaccine enhanced disease against respiratory syncytial virus Airway memory CD4 T cells


id: cord-288705-f3zqhpx1
type: PROTEIN
entity:
  Unfolded 748 Protein Response Negatively Regulates Transmissible Gastroenteritis Virus Replication by 749 Suppressing Protein


id: cord-342691-8jcfzexy
type: GGP
entity:
  IFIT2 MX1 IFITM1 DDX58 ISG15 OAS1 IRF9 IFIT5 IFIH1 IRF7 IFITM3 ISG20 IFIT3 IFITM2 IFI27 IFI16 IFI30 0


id: cord-321673-v5o49ees
type: DNA
entity:
  human respiratory syncytial virus hRSV small hydrophobic protein transmembrane domain The 3 dimensional structure


id: cord-309010-tmfm5u5h
type: PROTEIN
entity:
  secondary alkaline phosphataseconjugated goat anti rabbit 1 500 AP 1000 Vector Burlingame CA antibody


id: cord-309010-tmfm5u5h
type: GGP
entity:
  Streptococcus S pneumoniae Staphylococcus aureus Klebsiella pneumoniae Acinetobacter baumannii Legionella pneumophila Escherichia coli


id: cord-309010-tmfm5u5h
type: ORG
entity:
  Charité University of Berlin Justus Liebig University of Giessen Philipps University of Marburg University Hospital of Jena


id: cord-335871-zieuc7vk
type: WORK_OF_ART
entity:
  Alveolar Edema Must Be Cleared for the Acute Respiratory Distress Syndrome Patient to Survive Recruitment of the linear ubiquitin chain assembly


id: cord-310780-0k8owwf8
type: PROTEIN
entity:
  JNK c Jun aminoterminal kinase M matrix protein NF jB nuclear factor jB NA neuraminidase NP nucleoprotein NS1


id: cord-310780-0k8owwf8
type: GGP
entity:
  virus IFN interferon IPS 1 INF b promoter stimulator protein 1 IRF3 IFN regulatory factor 3 JNK c Jun aminoterminal kinase M matrix protein NF jB


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-310004-h9ixhhzz
type: PROTEIN
entity:
  human AP2M1 Abcam ab75995 anti actin Abcam ab8227 anti influenza NP Abcam ab104870 anti ZIKV NS3 GeneTex GTX133309 anti EV A71 2C GeneTex GTX132354 anti His tag Invitrogen MA1 21315 anti HA tag Abbkine A02040 anti Flag tag Sigma Aldrich F3165 anti Lamin A Abcam ab26300 anti glyceraldehyde 3 phosphate dehydrogenase GAPDH Abcam


id: cord-310004-h9ixhhzz
type: PROTEIN
entity:
  goat anti mouse immunoglobulin G H L antibody 1 500 Invitrogen A28175 and Alexa Fluor 594 goat rabbit 1 500 Invitrogen A27016


id: cord-310004-h9ixhhzz
type: DISEASE
entity:
  coronaviruses Severe acute respiratory syndrome coronavirus SARS CoV Middle East respiratory syndrome


id: cord-310004-h9ixhhzz
type: DISEASE
entity:
  influenza A H5N1 A tale of two cities Signaling mechanisms controlling cell fate and embryonic patterning Tollip


id: cord-309381-cb80ntxs
type: GGP
entity:
  IL 1R1 interleukin 1 receptor type 1 IL 10RB interleukin 10 receptor subunit beta IL 2RA interleukin 2 receptor subunit alpha IL 10RA interleukin 10 receptor subunit alpha IL 12RB2 interleukin 12 receptor subunit beta 2 IL 1RN interleukin 1 receptor antagonist TNFRSF1B TNF receptor


id: cord-309381-cb80ntxs
type: WORK_OF_ART
entity:
  NEP Modulation of Innate Immune Responses by the Influenza A NS1 and PA X Proteins Interplay of PA X


id: cord-339392-2ocz784l
type: DISEASE
entity:
  HIV type 2 Vpx protein and facilitate nuclear import of the pre integration complex 43 HIV type 1 Nef protein interacts with Hsp40 to enhance viral gene expression 44 Hsp40


id: cord-314825-fzba05wn
type: CELL_LINE
entity:
  China H5N1 H9N2 H4N1 H4N6 H5N3 H10N5 H4N8 H6N6 H7N9 United States H4N6 H6N2 H7N2 Canada H4N6 H3N3 South Korea H7N2 H5N2 Nigeria H5N1 and Egypt H5N1 H5N2 H9N2


id: cord-314825-fzba05wn
type: ORG
entity:
  Multitemperature Single Strand Conformational Polymorphism Serological Survey of the Influenza a Virus


id: cord-314825-fzba05wn
type: ORG
entity:
  Sequencing Provides Data for Stratifying Infection Prevention and Control Management of Nosocomial Influenza Rapid


id: cord-314825-fzba05wn
type: DISEASE
entity:
  H1N1 A H1N1 pdm09 None 311 312 Trinidad Tobago H3N2 A H1N1 pdm09 None 313 South America Argentina H1N1 H1N2 H3N2 A H1N1 pdm09 None 314 315 316 317 318 Brazil


id: cord-314825-fzba05wn
type: DISEASE
entity:
  influenza A H1N1 pdm09 viruses with M genes from human pandemic strains among Nigerian pigs Antigenic Detection of Human Strain of Influenza Virus A H3N2 in Swine Populations


id: cord-314825-fzba05wn
type: DISEASE
entity:
  H1N1 human influenza virus isolated from pigs in Japan Genomic reassortants of pandemic A H1N1 2009 virus and endemic porcine H1 and H3 viruses in swine in Japan Influenza A virus infection


id: cord-314825-fzba05wn
type: DISEASE
entity:
  H1N1 swine influenza virus isolated in Korea Phylogenetic analysis of swine influenza viruses recently isolated in Korea Isolation and characterization of novel H3N1 swine influenza viruses from pigs with respiratory diseases


id: cord-314825-fzba05wn
type: DISEASE
entity:
  influenza A virus in swine in two production systems in Guatemala Influenza Other Respir Diaz de Arce H Isolation


id: cord-325192-italbsed
type: ORG
entity:
  influenza virus membrane fusion Fusion of Mature HIV 1 Particles Leads to Complete Release of a Gag GFP


id: cord-338070-y8zi8iz9
type: PROTEIN
entity:
  Monocyte chemotactic protein 1 MCP 1 granulocyte colony stimulating factor G CSF chemokine C X C motif ligand 1


id: cord-347053-m5m4zgfy
type: PROTEIN
entity:
  IgG H L Alexa Fluor 488 and Alexa Fluor 568 A11029 and A11031 respectively goat anti rabbit IgG H L Alexa Fluor 488 A11034 and donkey


id: cord-347053-m5m4zgfy
type: PROTEIN
entity:
  Monocyte chemoattractant protein 1 MCP1 C C motif chemokine ligand 2 CCL3 alias Macrophage inflammatory protein 1


id: cord-347053-m5m4zgfy
type: ORG
entity:
  World Health Organization Pandemic Influenza Risk Management A WHO Guide to Inform and Harmonize National and International Pandemic Preparedness and Response World Health Organization Back


id: cord-347053-m5m4zgfy
type: LAW
entity:
  A Language and Environment for Statistical Computing Transepithelial endothelial Electrical Resistance


id: cord-324696-htx0ul4o
type: ORG
entity:
  Comparative Intestinal Histomorphology of Five Species of Phyllostomid Bats Phyllostomidae Microchiroptera Ecomorphological Relations


id: cord-333655-lylt7qld
type: PROTEIN
entity:
  ethanolamine PO 4 6Mana1 2Mana1 6Mana1 4GlcNa1 6myo inositol 1 PO 4 lipid Differential derivatization


id: cord-333655-lylt7qld
type: DISEASE
entity:
  human immunodeficiency virus type 1 HIV 1 and human langerin a C type lectin mainly expressed on Langerhans cells de Witte


id: cord-333655-lylt7qld
type: DISEASE
entity:
  human immunodeficiency virus type 1 gp120 V3 loop affects virus neutralization The alpha 1 2 mannosidase I inhibitor 1 deoxymannojirimycin


id: cord-333655-lylt7qld
type: DISEASE
entity:
  HIV 2 envelope glycoprotein Differential N linked glycosylation of human immunodeficiency virus and Ebola virus envelope glycoproteins


id: cord-333655-lylt7qld
type: DISEASE
entity:
  herpes simplex virus type 1 The multiple facets of HIV attachment to dendritic cell lectins Platelet activation


id: cord-333655-lylt7qld
type: DISEASE
entity:
  HIV on dendritic cell subsets Immunodeficiency virus uptake turnover and 2 phase transfer in human dendritic cells The M GP 5 glycoprotein complex of porcine reproductive and respiratory syndrome


id: cord-307148-k1uo3fxm
type: CELL_LINE
entity:
  AEC II alveolar epithelial cell types I and II DCs dendritic cells FOXO1 forkhead box O1 transcription factor FOXO3 forkhead box O3


id: cord-307148-k1uo3fxm
type: PROTEIN
entity:
  Glut3 glucose transporters 1 and 3 MCT monocarboxylate transporter NNT nicotinamide nucleotide transhydrogenase PDC pyruvate dehydrogenase complex 5


id: cord-307148-k1uo3fxm
type: PROTEIN
entity:
  nuclear respiratory factor 1 NRF1 Abbreviations Ac acetate ARE antioxidant response element CA9 carbonic anhydrase 9 CCR7 C C chemokine receptor type 7 ERR


id: cord-307148-k1uo3fxm
type: PROTEIN
entity:
  heme oxygenase 1 SOD2 263 NADP H quinone oxidoreductase NQO1 gamma glutamylcysteine synthetase GCLC thioredoxin TXN thioredoxin reductase 1 TXNRD1 264


id: cord-307148-k1uo3fxm
type: PROTEIN
entity:
  antioxidant transcriptional master regulator Nrf2 Nitric oxide donor S nitroso N acetylpenicillamine


id: cord-307148-k1uo3fxm
type: GGP
entity:
  box O3 transcription factor HIF 1α hypoxia inducible factor 1 alpha IFN interferon IL 6 interleukin 6 IRF3 IFN regulatory factor 3


id: cord-307148-k1uo3fxm
type: GGP
entity:
  carbonic anhydrase 9 CCR7 C C chemokine receptor type 7 ERR α estrogen related receptor alpha ETC electron transport chain K lysine


id: cord-307148-k1uo3fxm
type: GGP
entity:
  PPARG coactivator 1 alpha PHD2 prolyl hydroxylase domain protein 2 pVHL von Hippel Landau tumor suppressor protein SCOT OXCT1 succinyl CoA 3 oxaloacid CoA transferase


id: cord-307148-k1uo3fxm
type: GGP
entity:
  NADP H quinone oxidoreductase NQO1 gamma glutamylcysteine synthetase GCLC thioredoxin TXN thioredoxin reductase 1 TXNRD1


# bib

id: cord-000354-05lnj3w0
author: de Vries, Erik
date: 2011-03-31
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068995/
doi: 10.1371/journal.ppat.1001329
title:
  Dissection of the Influenza A Virus Endocytic Routes Reveals Macropinocytosis as an Alternative Entry Pathway

abstract:
  Influenza A virus (IAV) enters host cells upon binding of its hemagglutinin glycoprotein to sialylated host cell receptors. Whereas dynamin-dependent, clathrin-mediated endocytosis (CME) is generally considered as the IAV infection pathway, some observations suggest the occurrence of an as yet uncharacterized alternative entry route. By manipulating entry parameters we established experimental conditions that allow the separate analysis of dynamin-dependent and -independent entry of IAV. Whereas entry of IAV in phosphate-buffered saline could be completely inhibited by dynasore, a specific inhibitor of dynamin, a dynasore-insensitive entry pathway became functional in the presence of fetal calf serum. This finding was confirmed with the use of small interfering RNAs targeting dynamin-2. In the presence of serum, both IAV entry pathways were operational. Under these conditions entry could be fully blocked by combined treatment with dynasore and the amiloride derivative EIPA, the hallmark inhibitor of macropinocytosis, whereas either drug alone had no effect. The sensitivity of the dynamin-independent entry pathway to inhibitors or dominant-negative mutants affecting actomyosin dynamics as well as to a number of specific inhibitors of growth factor receptor tyrosine kinases and downstream effectors thereof all point to the involvement of macropinocytosis in IAV entry. Consistently, IAV particles and soluble FITC-dextran were shown to co-localize in cells in the same vesicles. Thus, in addition to the classical dynamin-dependent, clathrin-mediated endocytosis pathway, IAV enters host cells by a dynamin-independent route that has all the characteristics of macropinocytosis.


id: cord-000434-ff2zadol
author: Zhao, Rongmao
date: 2011-08-19
txt: ./txt/cord-000434-ff2zadol.txt
cache: ./cache/cord-000434-ff2zadol.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3158760/
doi: 10.1371/journal.pone.0023374
summary:
  The highly conserved H1 subtype-specific immunodominant epitope may form the basis for developing novel assays for sero-diagnosis and active surveillance against H1N1 IAVs. Influenza A viruses (IAVs), members of the Orthomyxoviridae family, are highly contagious to a variety of avian and mammalian species. To confirm that these antibodies can recognize the HA antigen, the reactivity of the anti-peptide sera were evaluated by Western blot and ELISA against the purified HA0 protein of H1N1pdm virus. The sensitivity and specificity of peptide-ELISA versus HI test was 96.5% and 74.4%, respectively, indicating the potential of the peptide-ELISA method in detecting antibody against H1-subtype IAVs. In the present study, we identified immunodominant linear B cell epitopes on the H1N1pdm virus HA protein by a peptide scanning approach using H1N1pdm patients sera. To screen the H1-subtype specific epitopes, a set of 50 peptides spanning the amino acid sequences of the HA protein ectodomain of pandemic A/H1N1 2009 (H1N1pdm) influenza virus strain A/ California/04/2009 were synthesized.

title:
  Identification of a Highly Conserved H1 Subtype-Specific Epitope with Diagnostic Potential in the Hemagglutinin Protein of Influenza A Virus

abstract:
  Subtype specificity of influenza A virus (IAV) is determined by its two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). For HA, 16 distinct subtypes (H1–H16) exist, while nine exist for NA. The epidemic strains of H1N1 IAV change frequently and cause annual seasonal epidemics as well as occasional pandemics, such as the notorious 1918 influenza pandemic. The recent introduction of pandemic A/H1N1 IAV (H1N1pdm virus) into humans re-emphasizes the public health concern about H1N1 IAV. Several studies have identified conserved epitopes within specific HA subtypes that can be used for diagnostics. However, immune specific epitopes in H1N1 IAV have not been completely assessed. In this study, linear epitopes on the H1N1pdm viral HA protein were identified by peptide scanning using libraries of overlapping peptides against convalescent sera from H1N1pdm patients. One epitope, P5 (aa 58–72) was found to be immunodominant in patients and to evoke high titer antibodies in mice. Multiple sequence alignments and in silico coverage analysis showed that this epitope is highly conserved in influenza H1 HA [with a coverage of 91.6% (9,860/10,767)] and almost completely absent in other subtypes [with a coverage of 3.3% (792/23,895)]. This previously unidentified linear epitope is located outside the five well-recognized antigenic sites in HA. A peptide ELISA method based on this epitope was developed and showed high correlation (χ(2) = 51.81, P<0.01, Pearson correlation coefficient R = 0.741) with a hemagglutination inhibition test. The highly conserved H1 subtype-specific immunodominant epitope may form the basis for developing novel assays for sero-diagnosis and active surveillance against H1N1 IAVs.


id: cord-002407-25cawzi0
title: Reverse Genetics Approaches for the Development of Influenza Vaccines
author: Nogales, Aitor
date: 2016-12-22
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297655/
doi: 10.3390/ijms18010020
abstract:
  Influenza viruses cause annual seasonal epidemics and occasional pandemics of human respiratory disease. Influenza virus infections represent a serious public health and economic problem, which are most effectively prevented through vaccination. However, influenza viruses undergo continual antigenic variation, which requires either the annual reformulation of seasonal influenza vaccines or the rapid generation of vaccines against potential pandemic virus strains. The segmented nature of influenza virus allows for the reassortment between two or more viruses within a co-infected cell, and this characteristic has also been harnessed in the laboratory to generate reassortant viruses for their use as either inactivated or live-attenuated influenza vaccines. With the implementation of plasmid-based reverse genetics techniques, it is now possible to engineer recombinant influenza viruses entirely from full-length complementary DNA copies of the viral genome by transfection of susceptible cells. These reverse genetics systems have provided investigators with novel and powerful approaches to answer important questions about the biology of influenza viruses, including the function of viral proteins, their interaction with cellular host factors and the mechanisms of influenza virus transmission and pathogenesis. In addition, reverse genetics techniques have allowed the generation of recombinant influenza viruses, providing a powerful technology to develop both inactivated and live-attenuated influenza vaccines. In this review, we will summarize the current knowledge of state-of-the-art, plasmid-based, influenza reverse genetics approaches and their implementation to provide rapid, convenient, safe and more effective influenza inactivated or live-attenuated vaccines.


id: cord-002823-n55xvwkf
author: Halstead, E. Scott
date: 2018-01-05
txt: ./txt/cord-002823-n55xvwkf.txt
cache: ./cache/cord-002823-n55xvwkf.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756339/
doi: 10.1186/s12931-017-0708-5
summary:
  The effect of local elevation of GM-CSF on IAV infection in the lung has been investigated in transgenic models with expression of GM-CSF under the control of constitutive or doxycycline-inducible promoters in lungs of alveolar or small airway epithelial cells of GM-CSF knockout (csf2 −/− ) mice [3, 4] . To examine the mechanism of protection conferred by therapeutic GM-CSF levels, we measured respiratory and biochemical parameters of lower airway disease, and analyzed the transcriptome of FACS-sorted AMs and exudative macrophages (EM) from IAV-infected mice. IPA also predicted the activation of the IL-10 receptor alpha-chain in both AMs and EMs. Given that IL-10 levels in BAL fluid were not elevated in DTGM as compared WT mice (Additional file 6: Figure S4D ), it is possible that GM-CSF overexpressing during IAV somehow potentiates IL-10 signaling in the lung microenvironment.

title:
  GM-CSF overexpression after influenza a virus infection prevents mortality and moderates M1-like airway monocyte/macrophage polarization

abstract:
  BACKGROUND: Influenza A viruses cause life-threatening pneumonia and lung injury in the lower respiratory tract. Application of high GM-CSF levels prior to infection has been shown to reduce morbidity and mortality from pathogenic influenza infection in mice, but the mechanisms of protection and treatment efficacy have not been established. METHODS: Mice were infected intranasally with influenza A virus (PR8 strain). Supra-physiologic levels of GM-CSF were induced in the airways using the double transgenic GM-CSF (DTGM) or littermate control mice starting on 3 days post-infection (dpi). Assessment of respiratory mechanical parameters was performed using the flexiVent rodent ventilator. RNA sequence analysis was performed on FACS-sorted airway macrophage subsets at 8 dpi. RESULTS: Supra-physiologic levels of GM-CSF conferred a survival benefit, arrested the deterioration of lung mechanics, and reduced the abundance of protein exudates in bronchoalveolar (BAL) fluid to near baseline levels. Transcriptome analysis, and subsequent validation ELISA assays, revealed that excess GM-CSF re-directs macrophages from an “M1-like” to a more “M2-like” activation state as revealed by alterations in the ratios of CXCL9 and CCL17 in BAL fluid, respectively. Ingenuity pathway analysis predicted that GM-CSF surplus during IAV infection elicits expression of anti-inflammatory mediators and moderates M1 macrophage pro-inflammatory signaling by Type II interferon (IFN-γ). CONCLUSIONS: Our data indicate that application of high levels of GM-CSF in the lung after influenza A virus infection alters pathogenic “M1-like” macrophage inflammation. These results indicate a possible therapeutic strategy for respiratory virus-associated pneumonia and acute lung injury. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12931-017-0708-5) contains supplementary material, which is available to authorized users.


id: cord-003169-bdw5ke4i
author: Guo, Hongbo
date: 2018-08-13
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107293/
doi: 10.1371/journal.ppat.1007233
title:
  Kinetic analysis of the influenza A virus HA/NA balance reveals contribution of NA to virus-receptor binding and NA-dependent rolling on receptor-containing surfaces

abstract:
  Interactions of influenza A virus (IAV) with sialic acid (SIA) receptors determine viral fitness and host tropism. Binding to mucus decoy receptors and receptors on epithelial host cells is determined by a receptor-binding hemagglutinin (HA), a receptor-destroying neuraminidase (NA) and a complex in vivo receptor-repertoire. The crucial but poorly understood dynamics of these multivalent virus-receptor interactions cannot be properly analyzed using equilibrium binding models and endpoint binding assays. In this study, the use of biolayer interferometric analysis revealed the virtually irreversible nature of IAV binding to surfaces coated with synthetic sialosides or engineered sialoglycoproteins in the absence of NA activity. In addition to HA, NA was shown to be able to contribute to the initial binding rate while catalytically active. Virus-receptor binding in turn contributed to receptor cleavage by NA. Multiple low-affinity HA-SIA interactions resulted in overall extremely high avidity but also permitted a dynamic binding mode, in which NA activity was driving rolling of virus particles over the receptor-surface. Virus dissociation only took place after receptor density of the complete receptor-surface was sufficiently decreased due to NA activity of rolling IAV particles. The results indicate that in vivo IAV particles, after landing on the mucus layer, reside continuously in a receptor-bound state while rolling through the mucus layer and over epithelial cell surfaces driven by the HA-NA-receptor balance. Quantitative BLI analysis enabled functional examination of this balance which governs this dynamic and motile interaction that is expected to be crucial for penetration of the mucus layer and subsequent infection of cells by IAV but likely also by other enveloped viruses carrying a receptor-destroying enzyme in addition to a receptor-binding protein.


id: cord-003498-4ct0ywnw
author: Bdeir, Najat
date: 2019-03-01
txt: ./txt/cord-003498-4ct0ywnw.txt
cache: ./cache/cord-003498-4ct0ywnw.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396908/
doi: 10.1371/journal.pone.0212757
summary:
  Defective interfering particles (DIPs) can be generated in IAV infected cells due to errors of the viral polymerase and may suppress spread of wild type (wt) virus. Here, we investigated whether coexpression of wt segments 2-8, PB2 protein and DI-244 RNA allows for production of DIPs. Employing a novel DI-244 variant encoding mScarlet-i, we show that DI-244-based DIPs are efficiently produced in cells expressing a codon optimized version of PB2 and that these DIPs exert potent antiviral activity. Influenza A viruses A/Panama/2007/99 (H3N2) [24] and A/PR/8/34 (H1N1) produced in embryonated chicken eggs were used to assess the antiviral activity of DIPs. We further employed a recombinant vesicular stomatitis virus (VSV) that expresses a dual reporter consisting of eGFP and firefly luciferase from an additional transcription unit located between the open reading frames for the viral glycoprotein and polymerase [27] .

title:
  A system for production of defective interfering particles in the absence of infectious influenza A virus

abstract:
  Influenza A virus (IAV) infection poses a serious health threat and novel antiviral strategies are needed. Defective interfering particles (DIPs) can be generated in IAV infected cells due to errors of the viral polymerase and may suppress spread of wild type (wt) virus. The antiviral activity of DIPs is exerted by a DI genomic RNA segment that usually contains a large deletion and suppresses amplification of wt segments, potentially by competing for cellular and viral resources. DI-244 is a naturally occurring prototypic segment 1-derived DI RNA in which most of the PB2 open reading frame has been deleted and which is currently developed for antiviral therapy. At present, coinfection with wt virus is required for production of DI-244 particles which raises concerns regarding biosafety and may complicate interpretation of research results. Here, we show that cocultures of 293T and MDCK cell lines stably expressing codon optimized PB2 allow production of DI-244 particles solely from plasmids and in the absence of helper virus. Moreover, we demonstrate that infectivity of these particles can be quantified using MDCK-PB2 cells. Finally, we report that the DI-244 particles produced in this novel system exert potent antiviral activity against H1N1 and H3N2 IAV but not against the unrelated vesicular stomatitis virus. This is the first report of DIP production in the absence of infectious IAV and may spur efforts to develop DIPs for antiviral therapy.


id: cord-003598-m2fsrwvw
title: Response Modifiers: Tweaking the Immune Response Against Influenza A Virus
author: Elbahesh, Husni
date: 2019-04-12
txt: ./txt/cord-003598-m2fsrwvw.txt
cache: ./cache/cord-003598-m2fsrwvw.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473099/
doi: 10.3389/fimmu.2019.00809
summary:
  Like many viruses, IAV is reliant on host factors and signaling-pathways for its replication, which could potentially offer alternative options to treat infections. Clinical treatment options for severe influenza virus infections remain limited and relying heavily on the administration of antiviral neuraminidase inhibitors (NAIs) and supportive critical care (9). While virus-targeted therapies remain the standard approach, IV''s mutability and adaptation to current antivirals has highlighted the need for new therapeutic options that target host factors that regulate IV infections and resulting immune responses. Host kinases regulate not only IAV entry and replication but also initiate antiviral signaling cascades that regulate expression of pro-inflammatory chemokines and cytokines during infections and present viable targets for intervention (24, (49) (50) (51) (52) (53) (54) (55) (56) (57) (58) . Inhibition of p38 mitogen-activated protein kinase impairs influenza virus-induced primary and secondary host gene responses and protects mice from lethal H5N1 infection

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-003639-bjtxf1y8
title: Influenza A virus surface proteins are organized to help penetrate host mucus
author: Vahey, Michael D
date: 2019-05-14
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516830/
doi: 10.7554/elife.43764
abstract:
  Influenza A virus (IAV) enters cells by binding to sialic acid on the cell surface. To accomplish this while avoiding immobilization by sialic acid in host mucus, viruses rely on a balance between the receptor-binding protein hemagglutinin (HA) and the receptor-cleaving protein neuraminidase (NA). Although genetic aspects of this balance are well-characterized, little is known about how the spatial organization of these proteins in the viral envelope may contribute. Using site-specific fluorescent labeling and super-resolution microscopy, we show that HA and NA are asymmetrically distributed on the surface of filamentous viruses, creating a spatial organization of binding and cleaving activities that causes viruses to step consistently away from their NA-rich pole. This Brownian ratchet-like diffusion produces persistent directional mobility that resolves the virus’s conflicting needs to both penetrate mucus and stably attach to the underlying cells, potentially contributing to the prevalence of the filamentous phenotype in clinical isolates of IAV.


id: cord-003772-1345qct4
author: Kummer, Susann
date: 2019-06-12
txt: ./txt/cord-003772-1345qct4.txt
cache: ./cache/cord-003772-1345qct4.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6631848/
doi: 10.3390/v11060548
summary:
  title: IFITM3 Clusters on Virus Containing Endosomes and Lysosomes Early in the Influenza A Infection of Human Airway Epithelial Cells To determine whether an IAV-induced viral membrane fusion and genome uncoating are required for the observed IFITM3 signal increase upon IAV infection, we performed experiments in the presence of Bafilomycin A1, specifically inhibiting endosomal acidification, or in the presence of Amantadine, specifically blocking the tetrameric M2 channel of IAV, thereby preventing genome uncoating. To determine whether an IAV-induced viral membrane fusion and genome uncoating are required for the observed IFITM3 signal increase upon IAV infection, we performed experiments in the presence of Bafilomycin A1, specifically inhibiting endosomal acidification, or in the presence of Amantadine, specifically blocking the tetrameric M2 channel of IAV, thereby preventing genome uncoating. A strong IFITM3 clustering with a ring-like appearance indicating vesicle coating was observed in both IAV-infected A549 cells ( Figure 5A ) and HSAEpCs at 10 h p.i.

title:
  IFITM3 Clusters on Virus Containing Endosomes and Lysosomes Early in the Influenza A Infection of Human Airway Epithelial Cells

abstract:
  Interferon-induced transmembrane proteins (IFITMs) have been shown to strongly affect influenza A virus (IAV) infectivity in tissue culture. Moreover, polymorphisms in IFITM3 have been associated with the severity of the disease in humans. IFITM3 appears to act early in the infection, but its mechanism of action and potential interactions with incoming IAV structures are not yet defined. Here, we visualized endogenous IFITM3 interactions with IAV in the human lung epithelial cell line A549 and in primary human airway epithelial cells employing stimulated emission depletion super-resolution microscopy. By applying an iterative approach for the cluster definition and computational cluster analysis, we found that IFITM3 reorganizes into clusters as IAV infection progresses. IFITM3 cluster formation started at 2-3 h post infection and increased over time to finally coat IAV-containing endosomal vesicles. This IAV-induced phenotype was due to the endosomal recruitment of IFITM3 rather than to an overall increase in the IFITM3 abundance. While the IAV-induced IFITM3 clustering and localization to endosomal vesicles was comparable in primary human airway epithelial cells and the human lung epithelial cell line A549, the endogenous IFITM3 signal was higher in primary cells. Moreover, we observed IFITM3 signals adjacent to IAV-containing recycling endosomes.


id: cord-003870-hr99dwi7
title: Host susceptibility to severe influenza A virus infection
author: Clohisey, Sara
date: 2019-09-05
txt: ./txt/cord-003870-hr99dwi7.txt
cache: ./cache/cord-003870-hr99dwi7.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6729070/
doi: 10.1186/s13054-019-2566-7
summary:
  Some demographic factors (pregnancy, obesity, and advanced age) appear to confer a more specific susceptibility to severe illness following infection with influenza viruses. Factors predicted to confer more specific susceptibility to influenza are placed higher in the diagram independently associated with severe disease from either seasonal or pandemic IAV [24] . Susceptibility to severe H1N1 infection was analysed in a recent genome-wide study (integrated with data on genetic variants associated with altered gene expression) which implicated an intronic SNP of GLDC, rs1755609-G [80] . Susceptible hosts may have impaired intracellular controls of viral replication (e.g. IFITM3, TMPRS22 variants), defective interferon responses (e.g. GLDC, IRF7/9 variants), or defects in cell-mediated immunity with increased baseline levels of systemic inflammation (obesity, pregnancy, advanced age). Susceptible hosts may have impaired intracellular controls of viral replication (e.g. IFITM3, TMPRS22 variants), defective interferon responses (e.g. GLDC, IRF7/9 variants), or defects in cell-mediated immunity with increased baseline levels of systemic inflammation (obesity, pregnancy, advanced age).

abstract:
  Most people exposed to a new flu virus do not notice any symptoms. A small minority develops critical illness. Some of this extremely broad variation in susceptibility is explained by the size of the initial inoculum or the influenza exposure history of the individual; some is explained by generic host factors, such as frailty, that decrease resilience following any systemic insult. Some demographic factors (pregnancy, obesity, and advanced age) appear to confer a more specific susceptibility to severe illness following infection with influenza viruses. As with other infectious diseases, a substantial component of susceptibility is determined by host genetics. Several genetic susceptibility variants have now been reported with varying levels of evidence. Susceptible hosts may have impaired intracellular controls of viral replication (e.g. IFITM3, TMPRS22 variants), defective interferon responses (e.g. GLDC, IRF7/9 variants), or defects in cell-mediated immunity with increased baseline levels of systemic inflammation (obesity, pregnancy, advanced age). These mechanisms may explain the prolonged viral replication reported in critically ill patients with influenza: patients with life-threatening disease are, by definition, abnormal hosts. Understanding these molecular mechanisms of susceptibility may in the future enable the design of host-directed therapies to promote resilience.


id: cord-003888-lgutt1r9
author: Lauterbach, Sarah E.
date: 2019-09-18
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749708/
doi: 10.1186/s13567-019-0684-5
title:
  Assessing exhibition swine as potential disseminators of infectious disease through the detection of five respiratory pathogens at agricultural exhibitions

abstract:
  Widespread geographic movement and extensive comingling of exhibition swine facilitates the spread and transmission of infectious pathogens. Nasal samples were collected from 2862 pigs at 102 exhibitions and tested for five pathogens. At least one pathogen was molecularly detected in pigs at 63 (61.8%) exhibitions. Influenza A virus was most prevalent and was detected in 498 (17.4%) samples. Influenza D virus was detected in two (0.07%) samples. More than one pathogen was detected in 165 (5.8%) samples. Influenza A virus remains a top threat to animal and human health, but other pathogens may be disseminated through the exhibition swine population.


id: cord-004018-33zi29bg
author: Coombs, Kevin M.
date: 2019-11-05
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893437/
doi: 10.3390/v11111028
title:
  Aptamer Profiling of A549 Cells Infected with Low-Pathogenicity and High-Pathogenicity Influenza Viruses

abstract:
  Influenza A viruses (IAVs) are important animal and human emerging and re-emerging pathogens that are responsible for yearly seasonal epidemics and sporadic pandemics. IAVs cause a wide range of clinical illnesses, from relatively mild infections by seasonal strains, to acute respiratory distress during infections with highly pathogenic avian IAVs (HPAI). For this study, we infected A549 human lung cells with lab prototype A/PR/8/34 (H1N1) (PR8), a seasonal H1N1 (RV733), the 2009 pandemic H1N1 (pdm09), or with two avian strains, an H5N1 HPAI strain or an H7N9 strain that has low pathogenicity in birds but high pathogenicity in humans. We used a newly-developed aptamer-based multiplexed technique (SOMAscan(®)) to examine >1300 human lung cell proteins affected by the different IAV strains, and identified more than 500 significantly dysregulated cellular proteins. Our analyses indicated that the avian strains induced more profound changes in the A549 global proteome compared to all tested low-pathogenicity H1N1 strains. The PR8 strain induced a general activation, primarily by upregulating many immune molecules, the seasonal RV733 and pdm09 strains had minimal effect upon assayed molecules, and the avian strains induced significant downregulation, primarily in antimicrobial response, cardiovascular and post-translational modification systems.


id: cord-004280-c470nlie
title: Airborne Influenza A Virus Exposure in an Elementary School
author: Coleman, Kristen K.
date: 2020-02-05
txt: ./txt/cord-004280-c470nlie.txt
cache: ./cache/cord-004280-c470nlie.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002614/
doi: 10.1038/s41598-020-58588-1
summary:
  In this study, we evaluated the use of a bioaerosol sampling method to noninvasively detect and quantify airborne influenza A virus (IAV) densities in a public elementary school. Significantly different (p = 0.049) airborne IAV densities were detected between all three indoor locations (i.e., gymnasium, classroom, and corridor) and all positive samples were collected during the last two weeks of 66 , and a 20-30% relative humidity level; Descriptive of an average elementary school student in the USA weighing ~23-32 kg with an assumed tidal volume (V T ) of 7 mL per kg of body mass. Given the high airborne IAV densities detected in the school corridor, along with elevated student contact rates, it is plausible to conclude that the school corridor is a "hotspot" for influenza virus transmission.

abstract:
  Influenza contributes significantly to childhood morbidity and mortality. Given the magnitude of the school-aged child population, a sizeable proportion of influenza virus transmission events are expected to occur within school settings. However, influenza virus activity in schools is not well-understood, likely due to our limited ability to accurately monitor for respiratory viruses without disrupting the school environment. In this study, we evaluated the use of a bioaerosol sampling method to noninvasively detect and quantify airborne influenza A virus (IAV) densities in a public elementary school. Air samples were collected from multiple locations in the school, two days per week, throughout an eight-week sampling period during influenza season. Real-time RT-PCR targeting the IAV M gene revealed detectable IAV on five occasions in densities ranging from 2.0 × 10(−1) to 1.9 × 10(4). No significant differences in IAV densities were related to student presence/absence. The majority of IAV-associated particles were ≤4 μm in diameter, and theoretical calculations indicate infectious thresholds after minutes of exposure. Our study represents the first identification and quantification of airborne influenza virus in an elementary school, and the results suggest that airborne IAV has the potential to circulate in schools during influenza season, in large enough doses known to cause infection.


id: cord-006362-7d5wzb7p
title: Influenza pathogenicity during pregnancy in women and animal models
author: van Riel, Debby
date: 2016-07-07
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101682/
doi: 10.1007/s00281-016-0580-2
abstract:
  Pregnant women are at the highest risk to develop severe and even fatal influenza. The high vulnerability of women against influenza A virus infections during pregnancy was repeatedly highlighted during influenza pandemics including the pandemic of this century. In 2009, mortality rates were particularly high among otherwise healthy pregnant women. However, our current understanding of the molecular mechanisms involved in severe disease development during pregnancy is still very limited. In this review, we summarize the knowledge on the clinical observations in influenza A virus-infected pregnant women. In addition, knowledge obtained from few existing experimental infections in pregnant animal models is discussed. Since clinical data do not provide in-depth information on the pathogenesis of severe influenza during pregnancy, adequate animal models are urgently required that mimic clinical findings. Studies in pregnant animal models will allow the dissection of involved molecular disease pathways that are key to improve patient management and care.


id: cord-007853-5xnft6pd
author: Lai, Yanni
date: 2020-04-04
txt: ./txt/cord-007853-5xnft6pd.txt
cache: ./cache/cord-007853-5xnft6pd.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125423/
doi: 10.1007/s12272-020-01230-5
summary:
  In the present study, we evaluated the antiviral effects of curcumin derivatives as potent inhibitors of influenza H1N1 neuraminidase based on 3D quantitative structure-activity relationship (QSAR) (Duarte et al. Confluent MDCK cell layers infected with 100 μL 100 TCID 50 IAV (H1N1) were treated with curcumin derivatives or oseltamivir carboxylate (20 mM, non-toxic concentration, data not shown) for 24 h. In this study, we used a 3D-QSAR model and docking model to investigate the inhibitory effects of curcumin derivatives against neuraminidase and influenza A/Font Monmouth/47(H1N1, FM1) in MDCK cells in vitro. We established a meaningful 3D-QSAR model (CoMFA) to study the SAR between curcumin derivatives and neuraminidase, and predicted the activity of the ligand in the test set. In addition, curcumin derivatives had different inhibitory effects on IAV neuraminidase protein, which was relative to their structures and binding models.

title:
  3D-quantitative structure–activity relationship and antiviral effects of curcumin derivatives as potent inhibitors of influenza H1N1 neuraminidase

abstract:
  Curcumin derivatives have been shown to inhibit replication of human influenza A viruses (IAVs). However, it is not clear whether curcumin and its derivatives can inhibit neuraminidase (NA) of influenza virus. In this study, a meaningful 3D quantitative structure–activity relationship model (comparative molecular field analysis R(2) = 0.997, q(2) = 0.527, s = 0.064, F = 282.663) was built to understand the chemical–biological interactions between their activities and neuraminidase. Molecular docking was used to predict binding models between curcumin derivatives and neuraminidase. Real-time polymerase chain reactions showed that the five active curcumin derivatives might have direct effects on viral particle infectivity in H1N1-infected lung epithelial (MDCK) cells. Neuraminidase activation assay showed that five active curcumin derivatives decreased H1N1-induced neuraminidase activation in MDCK cells. Indirect immunofluorescence assay indicated that two active curcumin derivatives (tetramethylcurcumin and curcumin) down-regulated the nucleoprotein expression. Curcumin inhibited IAV in vivo. The therapeutic mechanism of curcumin in the treatment of influenza viral pneumonia is related to improving the immune function of infected mice and regulating secretion of tumor necrosis-α, interleukin-6, and interferon-γ. These results indicate that curcumin derivatives inhibit IAV by blocking neuraminidase in the cellular model and curcumin also has anti-IAV activity in the animal model.


id: cord-011438-imbpgsub
title: Host–Virus Interaction: How Host Cells Defend against Influenza A Virus Infection
author: Zhang, Yun
date: 2020-03-29
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232439/
doi: 10.3390/v12040376
abstract:
  Influenza A viruses (IAVs) are highly contagious pathogens infecting human and numerous animals. The viruses cause millions of infection cases and thousands of deaths every year, thus making IAVs a continual threat to global health. Upon IAV infection, host innate immune system is triggered and activated to restrict virus replication and clear pathogens. Subsequently, host adaptive immunity is involved in specific virus clearance. On the other hand, to achieve a successful infection, IAVs also apply multiple strategies to avoid be detected and eliminated by the host immunity. In the current review, we present a general description on recent work regarding different host cells and molecules facilitating antiviral defenses against IAV infection and how IAVs antagonize host immune responses.


id: cord-013174-whg64w0w
author: Bhatta, Tarka Raj
date: 2020-09-10
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551734/
doi: 10.3390/v12091013
title:
  Infection Dynamics of Swine Influenza Virus in a Danish Pig Herd Reveals Recurrent Infections with Different Variants of the H1N2 Swine Influenza A Virus Subtype

abstract:
  Influenza A virus (IAV) in swine, so-called swine influenza A virus (swIAV), causes respiratory illness in pigs around the globe. In Danish pig herds, a H1N2 subtype named H1N2dk is one of the main circulating swIAV. In this cohort study, the infection dynamic of swIAV was evaluated in a Danish pig herd by sampling and PCR testing of pigs from two weeks of age until slaughter at 22 weeks of age. In addition, next generation sequencing (NGS) was used to identify and characterize the complete genome of swIAV circulating in the herd, and to examine the antigenic variability in the antigenic sites of the virus hemagglutinin (HA) and neuraminidase (NA) proteins. Overall, 76.6% of the pigs became PCR positive for swIAV during the study, with the highest prevalence at four weeks of age. Detailed analysis of the virus sequences obtained showed that the majority of mutations occurred at antigenic sites in the HA and NA proteins of the virus. At least two different H1N2 variants were found to be circulating in the herd; one H1N2 variant was circulating at the sow and nursery sites, while another H1N2 variant was circulating at the finisher site. Furthermore, it was demonstrated that individual pigs had recurrent swIAV infections with the two different H1N2 variants, but re-infection with the same H1N2 variant was also observed. Better understandings of the epidemiology, genetic and antigenic diversity of swIAV may help to design better health interventions for the prevention and control of swIAV infections in the herds.


id: cord-028887-eseo7lyh
title: Exploring heterologous prime-boost vaccination approaches to enhance influenza control in pigs
author: Li, Chong
date: 2020-07-09
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344353/
doi: 10.1186/s13567-020-00810-z
abstract:
  Influenza A viruses evolve rapidly to escape host immunity. In swine, this viral evolution has resulted in the emergence of multiple H1 and H3 influenza A virus (IAV) lineages in the United States (US) pig populations. The heterologous prime-boost vaccination strategy is a promising way to deal with diverse IAV infection in multiple animal models. However, whether or not this vaccination strategy is applicable to US swine to impart immunity against infection from North American strains of IAV is still unknown. We performed a vaccination-challenge study to evaluate the protective efficacy of using multivalent inactivated vaccine and/or a live attenuated IAV vaccine (LAIV) in pigs following multiple prime-boost vaccination protocols against a simultaneous H1N1 and H3N2 IAV infection. Our data show that pigs in the heterologous prime-boost vaccination group had more favorable outcomes consistent with a better response against virus challenge than non-vaccinated pigs. Additionally, delivering a multivalent heterologous inactivated vaccine boost to pigs following a single LAIV administration was also beneficial. We concluded the heterologous prime boost vaccination strategy may potentiate responses to suboptimal immunogens and holds the potential applicability to control IAV in the North American swine industry. However, more studies are needed to validate the application of this vaccination approach under field conditions.


id: cord-102458-7sssm3zk
author: Milanez-Almeida, Pedro
date: 2020-10-27
url: https://doi.org/10.1101/2020.10.27.357053
doi: 10.1101/2020.10.27.357053
title:
  Blood gene expression-based prediction of lethality after respiratory infection by influenza A virus in mice

abstract:
  Lethality after respiratory infection with influenza A virus (IAV) is associated with potent immune activation and lung tissue damage. In a well-controlled animal model of infection, we sought to determine if one could predict lethality using transcriptional information obtained from whole blood early after influenza virus exposure. We started with publicly available transcriptomic data from the lung, which is the primary site of the infection and pathology, to derive a multigene transcriptional signature of death reflective of innate inflammation associated with tissue damage. We refined this affected tissue signature with data from infected mouse and human blood to develop and validate a machine learning model that can robustly predict survival in mice after IAV challenge using data obtained from as little as 10 μl of blood from early time points post infection. Furthermore, in genetically identical, cohoused mice infected with the same viral bolus, the same model can predict the lethality of individual animals but, intriguingly, only within a specific time window that overlapped with the early effector phase of adaptive immunity. These findings raise the possibility of predicting disease outcome in respiratory virus infections with blood transcriptional data and pave the way for translating such approaches to humans.


id: cord-102471-dtukacm7
author: Xu, Y.
date: 2020-04-22
txt: ./txt/cord-102471-dtukacm7.txt
cache: ./cache/cord-102471-dtukacm7.txt
extension: .txt
mime: text/plain
url: http://medrxiv.org/cgi/content/short/2020.04.21.20073072v1?rss=1
doi: 10.1101/2020.04.21.20073072
summary:
  We have recently demonstrated proof-of-principle for a direct-from-sample Nanopore metagenomic sequencing protocol for influenza viruses with 83% sensitivity and 100% specificity compared to routine clinical diagnostic testing [15] . 21.20073072 doi: medRxiv preprint Here we describe Nanopore metagenomic sequencing directly from clinical respiratory samples at a UK hospital during the 2018/19 influenza season, evaluating the applicability of this approach in a routine laboratory as a test for influenza, and investigating where further optimisation is still required before the assay can be deployed in clinical practice. We assessed the performance of this experimental protocol head-to-head with routine clinical laboratory tests, and used the influenza sequence data to investigate drug resistance, genetic diversity, and nosocomial transmission events, demonstrating the diverse benefits that can be gained from a metagenomic approach to diagnostics. In this study, we conducted Nanopore metagenomic sequencing of IAV directly from clinical respiratory samples at a UK hospital during the 2018/19 influenza season, reporting a head-to-head comparison with routine clinical diagnostic tests.

title:
  Nanopore metagenomic sequencing of influenza virus directly from respiratory samples: diagnosis, drug resistance and nosocomial transmission

abstract:
  Background: Influenza virus presents a significant challenge to public health by causing seasonal epidemics and occasional pandemics. Nanopore metagenomic sequencing has the potential to be deployed for near-patient testing, providing rapid diagnosis of infection, rationalising antimicrobial therapy, and supporting interventions for infection control. This study aimed to evaluate the applicability of this sequencing approach as a routine laboratory test for influenza in clinical settings. Methods: We conducted Nanopore metagenomic sequencing for 180 respiratory samples from a UK hospital during the 2018/19 influenza season, and compared results to routine molecular diagnostic testing. We investigated drug resistance, genetic diversity, and nosocomial transmission using influenza sequence data. Results: Metagenomic sequencing was 83% (75/90) sensitive and 93% (84/90) specific for detecting influenza A viruses compared with the diagnostic standard (Cepheid Xpress/BioFire FilmArray Respiratory Panel). We identified a H3N2 genome with the oseltamivir resistant S331R mutation in the NA protein, potentially associated with the emergence of a distinct intra-subtype reassortant. Whole genome phylogeny refuted suspicions of a transmission cluster in the infectious diseases ward, but identified two other clusters that likely reflected nosocomial transmission, associated with a predominant strain circulating in the community. We also detected a range of other potentially pathogenic viruses and bacteria from the metagenome. Conclusion: Nanopore metagenomic sequencing can detect the emergence of novel variants and drug resistance, providing timely insights into antimicrobial stewardship and vaccine design. Generation of full genomes can contribute to the investigation and management of nosocomial outbreaks.


id: cord-102586-mx534xbx
title: Real Time Investigation of a large Nosocomial Influenza A Outbreak Informed by Genomic Epidemiology
author: Javaid, W.
date: 2020-05-15
url: http://medrxiv.org/cgi/content/short/2020.05.10.20096693v1?rss=1
doi: 10.1101/2020.05.10.20096693
abstract:
  Background: Nosocomial respiratory virus outbreaks represent serious public health challenges. Rapid and precise identification of cases and tracing of transmission chains is critical to end outbreaks and to inform prevention measures. Methods: We combined conventional surveillance with Influenza A virus (IAV) genome sequencing to identify and contain a large IAV outbreak in a metropolitan healthcare system. A total of 381 individuals, including 91 inpatients and 290 health care workers (HCWs), were included in the investigation. Results: During a 12-day period in early 2019, infection preventionists identified 89 HCWs and 18 inpatients as cases of influenza-like illness (ILI), using an amended definition, without the requirement for fever. Sequencing of IAV genomes from available nasopharyngeal (NP) specimens identified 66 individuals infected with a nearly identical strain of influenza A H1N1 (43 HCWs, 17 inpatients, and 6 with unspecified affiliation). All HCWs infected with the outbreak strain had received the seasonal influenza virus vaccination. Characterization of five representative outbreak viral isolates did not show antigenic drift. In conjunction with IAV genome sequencing, mining of electronic records pinpointed the origin of the outbreak as a single patient and a few interactions in the emergency department that occurred one day prior to the index ILI cluster. Conclusions: We used precision surveillance to identify and control a large nosocomial IAV outbreak, mapping the source of the outbreak to a single patient rather than HCWs as initially assumed based on conventional epidemiology. These findings have important ramifications for more effective prevention strategies to curb nosocomial respiratory virus outbreaks.


id: cord-255980-u0c6pg8n
author: Du, Lanying
date: 2010-07-02
txt: ./txt/cord-255980-u0c6pg8n.txt
cache: ./cache/cord-255980-u0c6pg8n.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0006291X10010946
doi: 10.1016/j.bbrc.2010.05.161
summary:
  Abstract The worldwide outbreak of the swine-origin 2009 H1N1 influenza A virus (IAV) and an increasing number of influenza cases caused by a highly pathogenic avian influenza (HPAI) H5N1 have accelerated the need to develop vaccines and antiviral agents against IAVs. Among various antivirals, neutralizing monoclonal antibodies (mAbs) are considered important passive therapeutics having an immediate effect against viral pathogens. As shown in Fig. 3A , 20 mAbs were initially screened for HA-specific antibody responses, 10 of which with the highest antibody titer were selected to detect neutralizing activity against five pseudoviruses expressing HA of H5N1 IAVs (QH-HA, XJ-HA, AH-HA, HK-HA, 1194-HA), one pseudovirus bearing HA of 2009 epidemic H1N1 IAV (H1N1-HA) ( Table 1) , and the VSV-G pseudovirus in 293T cells since this cell line demonstrated the highest ability to support virus infection.

title:
  Development of a safe and convenient neutralization assay for rapid screening of influenza HA-specific neutralizing monoclonal antibodies

abstract:
  Abstract The worldwide outbreak of the swine-origin 2009 H1N1 influenza A virus (IAV) and an increasing number of influenza cases caused by a highly pathogenic avian influenza (HPAI) H5N1 have accelerated the need to develop vaccines and antiviral agents against IAVs. Among various antivirals, neutralizing monoclonal antibodies (mAbs) are considered important passive therapeutics having an immediate effect against viral pathogens. Here we report a pseudovirus neutralization assay for rapid screening of neutralizing mAbs targeting hemagglutinin (HA) of H5N1 and H1N1 IAV. In this study, we generated six pseudoviruses with an HIV-1 backbone, respectively, expressing HA of four clades of H5N1 IAV and the 2009 epidemic H1N1 IAV. The resulting pseudoviruses were able to infect a variety of human and non-human cells, with 293T cells from human kidney as the most susceptible target cells. Using the established pseudovirus neutralization assay, we showed that three of ten selected mAbs specific to HA could potently neutralize infection of a pseudovirus bearing HA from the homologous IAV A/VietNam/1194/2004(H5N1) strain. This was highly consistent with the result of a microneutralization assay testing the same strain of a live IAV. Since the pseudovirus neutralization assay does not involve an infectious virus and can be performed without the requirement of a biosafety-3 laboratory, it may be applied for safe and rapid screening of neutralizing mAbs and antiviral agents targeting HA of IAVs.


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-267531-tqqj4cy0
author: He, Ying
date: 2014-05-14
url: https://doi.org/10.1111/irv.12257
doi: 10.1111/irv.12257
title:
  A 3-year prospective study of the epidemiology of acute respiratory viral infections in hospitalized children in Shenzhen, China

abstract:
  BACKGROUND: The epidemiology of local viral etiologies is essential for the management of viral respiratory tract infections. Limited data are available in China to describe the epidemiology of viral respiratory infections, especially in small–medium cities and rural areas. OBJECTIVES: To determine the viral etiology and seasonality of acute respiratory infections in hospitalized children, a 3-year study was conducted in Shenzhen, China. METHODS: Nasopharyngeal aspirates from eligible children were collected. Influenza and other respiratory viruses were tested by molecular assays simultaneously. Data were analyzed to describe the frequency and seasonality. RESULTS: Of the 2025 children enrolled in the study, 971 (48·0%) were positive for at least one viral pathogen, in which 890 (91·7%) were <4 years of age. The three most prevalent viruses were influenza A (IAV; 35·8%), respiratory syncytial virus (RSV; 30·5%) and human rhinovirus (HRV; 21·5%). Co-infections were found in 302 cases (31·1%), and dual viral infection was dominant. RSV, HRV and IAV were the most frequent viral agents involved in co-infection. On the whole, the obvious seasonal peaks mainly from March to May were observed with peak strength varying from 1 year to another. CONCLUSIONS: This study provides a basic profile of the epidemiology of acute respiratory viral infection in hospitalized children in Shenzhen. The spectrum of viruses in the study site is similar to that in other places, but the seasonality is closely related to geographic position, different from that in big cities in northern China and neighboring Hong Kong.


id: cord-272117-erzpz3c0
title: Dissecting host cell death programs in the pathogenesis of influenza
author: Downey, Jeffrey
date: 2018-04-18
url: https://api.elsevier.com/content/article/pii/S1286457918300935
doi: 10.1016/j.micinf.2018.03.005
abstract:
  Influenza A virus (IAV) is a pulmonary pathogen, responsible for significant yearly morbidity and mortality. Due to the absence of highly effective antiviral therapies and vaccine, as well as the constant threat of an emerging pandemic strain, there is considerable need to better understand the host–pathogen interactions and the factors that dictate a protective versus detrimental immune response to IAV. Even though evidence of IAV-induced cell death in human pulmonary epithelial and immune cells has been observed for almost a century, very little is known about the consequences of cell death on viral pathogenesis. Recent study indicates that both the type of cell death program and its kinetics have major implications on host defense and survival. In this review, we discuss advances in our understanding of cell death programs during influenza virus infection, in hopes of fostering new areas of investigation for targeted clinical intervention.


id: cord-275821-yu39aw54
title: Novel insights into bat influenza A viruses
author: Ciminski, Kevin
date: 2017-09-14
url: https://doi.org/10.1099/jgv.0.000927
doi: 10.1099/jgv.0.000927
abstract:
  In 2012 and 2013, influenza virus genome sequences of two new influenza A virus (IAV) subtypes were discovered in bat specimens, but further characterization was largely impeded by the lack of infectious virus. With the identification of highly susceptible cell lines, reconstitution of infectious bat IAV by reverse genetics recently succeeded and allowed a first insight into the life cycle of these viruses. Although there is a certain degree of functional compatibility between bat and conventional influenza A virus proteins, there are striking differences, including receptor usage, polarity of infection and reassortment potential.


id: cord-278465-tjjkz16y
title: Urbanization and the dynamics of RNA viruses in Mallards (Anas platyrhynchos)
author: Wille, Michelle
date: 2017-03-18
url: https://www.ncbi.nlm.nih.gov/pubmed/28323070/
doi: 10.1016/j.meegid.2017.03.019
abstract:
  Urbanization is intensifying worldwide, and affects the epidemiology of infectious diseases. However, the effect of urbanization on natural host-pathogen systems remains poorly understood. Urban ducks occupy an interesting niche in that they directly interact with both humans and wild migratory birds, and either directly or indirectly with food production birds. Here we have collected samples from Mallards (Anas platyrhynchos) residing in a pond in central Uppsala, Sweden, from January 2013 to January 2014. This artificial pond is kept ice-free during the winter months, and is a popular location where the ducks are fed, resulting in a resident population of ducks year-round. Nine hundred and seventy seven (977) fecal samples were screened for RNA viruses including: influenza A virus (IAV), avian paramyxovirus 1, avian coronavirus (CoV), and avian astrovirus (AstroV). This intra-annual dataset illustrates that these RNA viruses exhibit similar annual patterns to IAV, suggesting similar ecological factors are at play. Furthermore, in comparison to wild ducks, autumnal prevalence of IAV and CoV are lower in this urban population. We also demonstrate that AstroV might be a larger burden to urban ducks than IAV, and should be better assessed to demonstrate the degree to which wild birds contribute to the epidemiology of these viruses. The presence of economically relevant viruses in urban Mallards highlights the importance of elucidating the ecology of wildlife pathogens in urban environments, which will become increasingly important for managing disease risks to wildlife, food production animals, and humans.


id: cord-278523-djjtgbh6
author: Zhou, Bei-xian
date: 2020-06-05
url: https://doi.org/10.1038/s41401-020-0403-9
doi: 10.1038/s41401-020-0403-9
title:
  β-sitosterol ameliorates influenza A virus-induced proinflammatory response and acute lung injury in mice by disrupting the cross-talk between RIG-I and IFN/STAT signaling

abstract:
  β-Sitosterol (24-ethyl-5-cholestene-3-ol) is a common phytosterol Chinese medical plants that has been shown to possess antioxidant and anti-inflammatory activity. In this study we investigated the effects of β-sitosterol on influenza virus-induced inflammation and acute lung injury and the molecular mechanisms. We demonstrate that β-sitosterol (150–450 μg/mL) dose-dependently suppresses inflammatory response through NF-κB and p38 mitogen-activated protein kinase (MAPK) signaling in influenza A virus (IAV)-infected cells, which was accompanied by decreased induction of interferons (IFNs) (including Type I and III IFN). Furthermore, we revealed that the anti-inflammatory effect of β-sitosterol resulted from its inhibitory effect on retinoic acid-inducible gene I (RIG-I) signaling, led to decreased STAT1 signaling, thus affecting the transcriptional activity of ISGF3 (interferon-stimulated gene factor 3) complexes and resulting in abrogation of the IAV-induced proinflammatory amplification effect in IFN-sensitized cells. Moreover, β-sitosterol treatment attenuated RIG-I-mediated apoptotic injury of alveolar epithelial cells (AEC) via downregulation of pro-apoptotic factors. In a mouse model of influenza, pre-administration of β-sitosterol (50, 200 mg·kg(−1)·d(−1), i.g., for 2 days) dose-dependently ameliorated IAV-mediated recruitment of pathogenic cytotoxic T cells and immune dysregulation. In addition, pre-administration of β-sitosterol protected mice from lethal IAV infection. Our data suggest that β-sitosterol blocks the immune response mediated by RIG-I signaling and deleterious IFN production, providing a potential benefit for the treatment of influenza.


id: cord-286741-h3oix9zc
title: Animal models for the risk assessment of viral pandemic potential
author: Park, Mee Sook
date: 2020-04-22
txt: ./txt/cord-286741-h3oix9zc.txt
cache: ./cache/cord-286741-h3oix9zc.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1186/s42826-020-00040-6
doi: 10.1186/s42826-020-00040-6
summary:
  Focusing on the pandemic potential of viral infectious diseases, we suggest what should be assessed to prevent global catastrophes from influenza virus, Middle East respiratory syndrome coronavirus, dengue and Zika viruses. When a virus with a nonhuman origin HA and an efficient human transmissibility gets transmitted from the adaptation host swine to human (4), a pandemic might ensue (5) of IAVs, avian and swine species should be considered the natural reservoir animals, and in case of MERS-CoVs, bats and dromedary camels [32, 87, 90] . In addition to NHP and hDPP4-mouse models, rabbits might be a good candidate for MERS-CoV transmission experiments due to its camel-like receptor distribution in the upper respiratory tract (Table 2 ) [142, 150] . Human-like symptoms of MERS-CoV infection have not been reproduced in other animals than hDPP4-mice and NHPs. Starting from the distinct receptor specificities of the HA proteins between avian and human IAVs, host restriction determinants of IAVs have been documented [56] .

abstract:
  Pandemics affect human lives severely and globally. Experience predicts that there will be a pandemic for sure although the time is unknown. When a viral epidemic breaks out, assessing its pandemic risk is an important part of the process that characterizes genomic property, viral pathogenicity, transmission in animal model, and so forth. In this review, we intend to figure out how a pandemic may occur by looking into the past influenza pandemic events. We discuss interpretations of the experimental evidences resulted from animal model studies and extend implications of viral pandemic potentials and ingredients to emerging viral epidemics. Focusing on the pandemic potential of viral infectious diseases, we suggest what should be assessed to prevent global catastrophes from influenza virus, Middle East respiratory syndrome coronavirus, dengue and Zika viruses.


id: cord-288705-f3zqhpx1
author: Slaine, Patrick
date: 2020-10-01
txt: ./txt/cord-288705-f3zqhpx1.txt
cache: ./cache/cord-288705-f3zqhpx1.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.09.30.319863
doi: 10.1101/2020.09.30.319863
summary:
  title: Thiopurines activate an antiviral unfolded protein response that blocks viral glycoprotein accumulation in cell culture infection model Selective disruption of IAV glycoprotein processing and accumulation by 6-TG and 6-TGo correlated with unfolded protein response (UPR) activation and HA accumulation could be partially restored by the chemical chaperone 4-phenylbutyrate (4PBA). Thiopurines inhibited replication of the human coronavirus OC43 (HCoV-OC43), which also correlated with UPR/ISR activation and diminished accumulation of ORF1ab and nucleocapsid (N) mRNAs and N protein, which suggests broader disruption of coronavirus gene expression in ER-derived cytoplasmic compartments. Our results suggest that 406 the effects are unlikely to be mediated through DNA or RNA incorporation of 6-TG because 1) 407 replicative stress does not specifically induce UPR; 2) among viral proteins, glycoprotein 408 accumulation and processing was preferentially disrupted; 3) messenger RNA levels of HA and 409 NA were not affected.

title:
  Thiopurines activate an antiviral unfolded protein response that blocks viral glycoprotein accumulation in cell culture infection model

abstract:
  Enveloped viruses, including influenza A viruses (IAVs) and coronaviruses (CoVs), utilize the host cell secretory pathway to synthesize viral glycoproteins and direct them to sites of assembly. Using an image-based high-content screen, we identified two thiopurines, 6-thioguanine (6-TG) and 6-thioguanosine (6-TGo), that selectively disrupted the processing and accumulation of IAV glycoproteins hemagglutinin (HA) and neuraminidase (NA). Selective disruption of IAV glycoprotein processing and accumulation by 6-TG and 6-TGo correlated with unfolded protein response (UPR) activation and HA accumulation could be partially restored by the chemical chaperone 4-phenylbutyrate (4PBA). Chemical inhibition of the integrated stress response (ISR) restored accumulation of NA monomers in the presence of 6-TG or 6-TGo, but did not restore NA glycosylation or oligomerization. Thiopurines inhibited replication of the human coronavirus OC43 (HCoV-OC43), which also correlated with UPR/ISR activation and diminished accumulation of ORF1ab and nucleocapsid (N) mRNAs and N protein, which suggests broader disruption of coronavirus gene expression in ER-derived cytoplasmic compartments. The chemically similar thiopurine 6-mercaptopurine (6-MP) had little effect on the UPR and did not affect IAV or HCoV-OC43 replication. Consistent with reports on other CoV Spike (S) proteins, ectopic expression of SARS-CoV-2 S protein caused UPR activation. 6-TG treatment inhibited accumulation of full length S0 or furin-cleaved S2 fusion proteins, but spared the S1 ectodomain. DBeQ, which inhibits the p97 AAA-ATPase required for retrotranslocation of ubiquitinated misfolded proteins during ER-associated degradation (ERAD) restored accumulation of S0 and S2 proteins in the presence of 6-TG, suggesting that 6-TG induced UPR accelerates ERAD-mediated turnover of membrane-anchored S0 and S2 glycoproteins. Taken together, these data indicate that 6-TG and 6-TGo are effective host-targeted antivirals that trigger the UPR and disrupt accumulation of viral glycoproteins. Importantly, our data demonstrate for the first time the efficacy of these thiopurines in limiting IAV and HCoV-OC43 replication in cell culture models. IMPORTANCE Secreted and transmembrane proteins are synthesized in the endoplasmic reticulum (ER), where they are folded and modified prior to transport. During infection, many viruses burden the ER with the task of creating and processing viral glycoproteins that will ultimately be incorporated into viral envelopes. Some viruses refashion the ER into replication compartments where viral gene expression and genome replication take place. This viral burden on the ER can trigger the cellular unfolded protein response (UPR), which attempts to increase the protein folding and processing capacity of the ER to match the protein load. Much remains to be learned about how viruses co-opt the UPR to ensure efficient synthesis of viral glycoproteins. Here, we show that two FDA-approved thiopurine drugs, 6-TG and 6-TGo, induce the UPR in a manner that impedes viral glycoprotein accumulation for enveloped influenza viruses and coronaviruses. These drugs may impede the replication of viruses that require precise tuning of the UPR to support viral glycoprotein synthesis for the successful completion of a replication cycle.


id: cord-291014-cfnoxhtd
author: Zheng, Jian
date: 2018-02-28
url: https://doi.org/10.1016/j.coviro.2017.11.002
doi: 10.1016/j.coviro.2017.11.002
title:
  Immune responses in influenza A virus and human coronavirus infections: an ongoing battle between the virus and host

abstract:
  Respiratory viruses, especially influenza A viruses and coronaviruses such as MERS-CoV, represent continuing global threats to human health. Despite significant advances, much needs to be learned. Recent studies in virology and immunology have improved our understanding of the role of the immune system in protection and in the pathogenesis of these infections and of co-evolution of viruses and their hosts. These findings, together with sophisticated molecular structure analyses, omics tools and computer-based models, have helped delineate the interaction between respiratory viruses and the host immune system, which will facilitate the development of novel treatment strategies and vaccines with enhanced efficacy.


id: cord-291534-c6cjxq07
title: Cationic Host Defence Peptides: Potential as Antiviral Therapeutics
author: Gwyer Findlay, Emily
date: 2013-05-07
url: https://doi.org/10.1007/s40259-013-0039-0
doi: 10.1007/s40259-013-0039-0
abstract:
  There is a pressing need to develop new antiviral treatments; of the 60 drugs currently available, half are aimed at HIV-1 and the remainder target only a further six viruses. This demand has led to the emergence of possible peptide therapies, with 15 currently in clinical trials. Advancements in understanding the antiviral potential of naturally occurring host defence peptides highlights the potential of a whole new class of molecules to be considered as antiviral therapeutics. Cationic host defence peptides, such as defensins and cathelicidins, are important components of innate immunity with antimicrobial and immunomodulatory capabilities. In recent years they have also been shown to be natural, broad-spectrum antivirals against both enveloped and non-enveloped viruses, including HIV-1, influenza virus, respiratory syncytial virus and herpes simplex virus. Here we review the antiviral properties of several families of these host peptides and their potential to inform the design of novel therapeutics.


id: cord-296890-08kqtw8s
author: Toh, Teck-Hock
date: 2019-02-13
txt: ./txt/cord-296890-08kqtw8s.txt
cache: ./cache/cord-296890-08kqtw8s.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1093/ofid/ofz074
doi: 10.1093/ofid/ofz074
summary:
  Specimens were examined at our collaborating institutions with a panel of molecular assays for viral pathogens including influenza A (IAV), IBV, ICV, and IDV, human adenovirus (AdV), human enterovirus (EV), human coronavirus (CoV), respiratory syncytial virus subtype A (RSV-A) or RSV-B, and parainfluenza virus (PIV) types 1–4. One study of respiratory samples collected from children living in Kuala Lumpur under 5 years of age between 1982 and 2008 found that 26.4% of the samples were positive by immunofluorescence assays and viral cultures for viral pathogens, with a prevalence of 18.6% for respiratory syncytial virus (RSV), 3.5% for parainfluenza viruses (PIVs), 2.9% for influenza viruses, and 1.37% for adenovirus [10] . The overall objective of this study was to examine the viral etiology of and risk factors for pneumonia among patients admitted to Sibu and Kapit Hospitals between June 2017 and May 2018 and, in doing so, to assist Malaysian collaborators with setting up sustainable real-time molecular assays for viral respiratory pathogens.

title:
  High Prevalence of Viral Infections Among Hospitalized Pneumonia Patients in Equatorial Sarawak, Malaysia

abstract:
  BACKGROUND: Although pneumonia is a known cause of morbidity and mortality in Sarawak, Malaysia, the etiology and epidemiology of pneumonia are not well described in this equatorial region. Routine clinical diagnostics for pneumonia etiology at government hospitals in Sarawak had historically involved only bacterial diagnostics. Viral diagnostics were only obtained through outside consultations. METHODS: From June 15, 2017 to May 14, 2018, we collected nasopharyngeal swabs from 600 patients of all ages older than 1 month hospitalized with pneumonia at Sibu and Kapit Hospitals. Specimens were examined at our collaborating institutions with a panel of molecular assays for viral pathogens including influenza A (IAV), IBV, ICV, and IDV, human adenovirus (AdV), human enterovirus (EV), human coronavirus (CoV), respiratory syncytial virus subtype A (RSV-A) or RSV-B, and parainfluenza virus (PIV) types 1–4. RESULTS: Of 599 samples examined, 288 (48%) had molecular evidence of 1 or more respiratory viruses. Overall, the most prevalent virus detected was RSV-A (14.2%) followed by AdV (10.4%) and IAV (10.4%), then RSV-B (6.2%), EV (4.2%), IBV (2.2%), PIV-3 (1.7%), CoV (1.0%), PIV-1 (1.0%), PIV-4 (0.7%), and PIV-2 (0.2%). No specimens were confirmed positive for ICV or IDV. CONCLUSIONS: The high prevalence of viruses detected in this study suggest that respiratory viruses may be responsible for considerable morbidity in equatorial regions such as Sarawak. Access to viral diagnostics are very necessary for medical staff to determine appropriate pneumonia treatments.


id: cord-298458-p7rvupjo
title: The CD8 T Cell Response to Respiratory Virus Infections
author: Schmidt, Megan E.
date: 2018-04-09
url: https://doi.org/10.3389/fimmu.2018.00678
doi: 10.3389/fimmu.2018.00678
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-300423-q2i328sz
title: Co-infection of influenza A virus enhances SARS-CoV-2 infectivity
author: Bai, Lei
date: 2020-10-14
txt: ./txt/cord-300423-q2i328sz.txt
cache: ./cache/cord-300423-q2i328sz.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.10.14.335893
doi: 10.1101/2020.10.14.335893
summary:
  Remarkably, increased SARS-CoV-2 viral load and more severe lung damage were observed in mice co-infected with IAV in vivo. The results demonstrate that the pre-infection of 57 IAV strongly enhances the infectivity of SARS-CoV-2 by boosting viral entry in the cells 58 and by elevating viral load plus more severe lung damage in infected mice. We 75 further tested more cell lines to show that the enhancement of the pSARS-CoV-2 infectivity 76 by IAV was a general effect although the increased folds were different (lower basal level 77 of infectivity, higher enhancement fold) (Fig.1D ). We found that the pre-infection of IAV 80 strongly increased the copy numbers of the SARS-CoV-2 genome (E and N genes) in both 81 cell lysates and supernatants of A549 (~15 folds) (Fig.1F) . The histological data in Fig. 2D further illustrated that IAV and 98 SARS-CoV-2 co-infection induced more severe lung pathologic changes with massive 99 infiltrating cells and obvious alveolar necrosis as compared to SARS-CoV-2 single 100 infection or mock infection.

abstract:
  The upcoming flu season in the northern hemisphere merging with the current COVID-19 pandemic raises a potentially severe threat to public health. Through experimental co-infection of IAV with either pseudotyped or SARS-CoV-2 live virus, we found that IAV pre-infection significantly promoted the infectivity of SARS-CoV-2 in a broad range of cell types. Remarkably, increased SARS-CoV-2 viral load and more severe lung damage were observed in mice co-infected with IAV in vivo. Moreover, such enhancement of SARS-CoV-2 infectivity was not seen with several other viruses probably due to a unique IAV segment as an inducer to elevate ACE2 expression. This study illustrates that IAV has a special nature to aggravate SARS-CoV-2 infection, and prevention of IAV is of great significance during the COVID-19 pandemic.


id: cord-307148-k1uo3fxm
title: COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm
author: Bradshaw, Patrick C.
date: 2020-09-09
txt: ./txt/cord-307148-k1uo3fxm.txt
cache: ./cache/cord-307148-k1uo3fxm.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33014275/
doi: 10.1155/2020/6401341
summary:
  R-BHB activates anti-inflammatory GPR109A signaling and inhibits the NLRP3 inflammasome and histone deacetylases, while a ketogenic diet has been shown to protect mice from influenza virus infection through a protective γδ T cell response and by increasing electron transport chain gene expression to restore energy metabolism. Others have also suggested that increasing systemic ketone levels may aid host defenses against respiratory viral infection, in part, by decreasing inflammation [1, 2] , including a recent comprehensive review [3] , while a clinical trial of the effects of a ketogenic diet on intubated SARS-CoV-2 patients has recently been registered (NCT04358835). Coronaviruses have been shown to increase the oxidation of phospholipids, which stimulate toll-like receptor 4 (TLR4) signaling on macrophages, leading to cytokine production and acute lung injury [163] , so HDAC inhibition with R-BHB appears to be a viable treatment to decrease cytokine levels and inflammation.

abstract:
  Human SARS-CoV-2 infection is characterized by a high mortality rate due to some patients developing a large innate immune response associated with a cytokine storm and acute respiratory distress syndrome (ARDS). This is characterized at the molecular level by decreased energy metabolism, altered redox state, oxidative damage, and cell death. Therapies that increase levels of (R)-beta-hydroxybutyrate (R-BHB), such as the ketogenic diet or consuming exogenous ketones, should restore altered energy metabolism and redox state. R-BHB activates anti-inflammatory GPR109A signaling and inhibits the NLRP3 inflammasome and histone deacetylases, while a ketogenic diet has been shown to protect mice from influenza virus infection through a protective γδ T cell response and by increasing electron transport chain gene expression to restore energy metabolism. During a virus-induced cytokine storm, metabolic flexibility is compromised due to increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that damage, downregulate, or inactivate many enzymes of central metabolism including the pyruvate dehydrogenase complex (PDC). This leads to an energy and redox crisis that decreases B and T cell proliferation and results in increased cytokine production and cell death. It is hypothesized that a moderately high-fat diet together with exogenous ketone supplementation at the first signs of respiratory distress will increase mitochondrial metabolism by bypassing the block at PDC. R-BHB-mediated restoration of nucleotide coenzyme ratios and redox state should decrease ROS and RNS to blunt the innate immune response and the associated cytokine storm, allowing the proliferation of cells responsible for adaptive immunity. Limitations of the proposed therapy include the following: it is unknown if human immune and lung cell functions are enhanced by ketosis, the risk of ketoacidosis must be assessed prior to initiating treatment, and permissive dietary fat and carbohydrate levels for exogenous ketones to boost immune function are not yet established. The third limitation could be addressed by studies with influenza-infected mice. A clinical study is warranted where COVID-19 patients consume a permissive diet combined with ketone ester to raise blood ketone levels to 1 to 2 mM with measured outcomes of symptom severity, length of infection, and case fatality rate.


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-309010-tmfm5u5h
title: Spectrum of pathogen- and model-specific histopathologies in mouse models of acute pneumonia
author: Dietert, Kristina
date: 2017-11-20
url: https://doi.org/10.1371/journal.pone.0188251
doi: 10.1371/journal.pone.0188251
abstract:
  Pneumonia may be caused by a wide range of pathogens and is considered the most common infectious cause of death in humans. Murine acute lung infection models mirror human pathologies in many aspects and contribute to our understanding of the disease and the development of novel treatment strategies. Despite progress in other fields of tissue imaging, histopathology remains the most conclusive and practical read out tool for the descriptive and semiquantitative evaluation of mouse pneumonia and therapeutic interventions. Here, we systematically describe and compare the distinctive histopathological features of established models of acute pneumonia in mice induced by Streptococcus (S.) pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Legionella pneumophila, Escherichia coli, Middle East respiratory syndrome (MERS) coronavirus, influenza A virus (IAV) and superinfection of IAV-incuced pneumonia with S. pneumoniae. Systematic comparisons of the models revealed striking differences in the distribution of lesions, the characteristics of pneumonia induced, principal inflammatory cell types, lesions in adjacent tissues, and the detectability of the pathogens in histological sections. We therefore identified core criteria for each model suitable for practical semiquantitative scoring systems that take into account the pathogen- and model-specific patterns of pneumonia. Other critical factors that affect experimental pathologies are discussed, including infectious dose, time kinetics, and the genetic background of the mouse strain. The substantial differences between the model-specific pathologies underscore the necessity of pathogen- and model-adapted criteria for the comparative quantification of experimental outcomes. These criteria also allow for the standardized validation and comparison of treatment strategies in preclinical models.


id: cord-309381-cb80ntxs
title: Host Single Nucleotide Polymorphisms Modulating Influenza A Virus Disease in Humans
author: Nogales, Aitor
date: 2019-09-30
txt: ./txt/cord-309381-cb80ntxs.txt
cache: ./cache/cord-309381-cb80ntxs.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3390/pathogens8040168
doi: 10.3390/pathogens8040168
summary:
  IAV RNAs are mainly recognized by the endosomal, membrane-associated PRR Toll-like receptors (TLRs) 3 (double-stranded RNAs, dsRNAs) or 7/8 (ssRNAs), respectively [50, 51] , by the cytoplasmic PRR retinoic acid-inducible gene I (RIG-I), which detects dsRNA and 5 -triphosphates of the negative ssRNA viral genome [50, 52] , generated during replication of multiple viruses, by the NOD-like receptor family member NOD-, LRR-and pyrin domain-containing 3 (NLRP3), which recognizes various stimuli (see below) [53] and by the absent in melanoma 2 (AIM2) protein, recognizing not well-characterized influenza stimuli [54] . Another important SNP (rs34481144) associated with risk of severe influenza in humans from the United States (US) infected with seasonal IAVs is located in the 5 -UTR of the IFITM3 gene [123, 124] .

abstract:
  A large number of human genes associated with viral infections contain single nucleotide polymorphisms (SNPs), which represent a genetic variation caused by the change of a single nucleotide in the DNA sequence. SNPs are located in coding or non-coding genomic regions and can affect gene expression or protein function by different mechanisms. Furthermore, they have been linked to multiple human diseases, highlighting their medical relevance. Therefore, the identification and analysis of this kind of polymorphisms in the human genome has gained high importance in the research community, and an increasing number of studies have been published during the last years. As a consequence of this exhaustive exploration, an association between the presence of some specific SNPs and the susceptibility or severity of many infectious diseases in some risk population groups has been found. In this review, we discuss the relevance of SNPs that are important to understand the pathology derived from influenza A virus (IAV) infections in humans and the susceptibility of some individuals to suffer more severe symptoms. We also discuss the importance of SNPs for IAV vaccine effectiveness.


id: cord-310004-h9ixhhzz
author: Yuan, Shuofeng
date: 2020-08-28
url: https://www.ncbi.nlm.nih.gov/pubmed/32923629/
doi: 10.1126/sciadv.aba7910
title:
  Viruses harness YxxØ motif to interact with host AP2M1 for replication: A vulnerable broad-spectrum antiviral target

abstract:
  Targeting a universal host protein exploited by most viruses would be a game-changing strategy that offers broad-spectrum solution and rapid pandemic control including the current COVID-19. Here, we found a common YxxØ-motif of multiple viruses that exploits host AP2M1 for intracellular trafficking. A library chemical, N-(p-amylcinnamoyl)anthranilic acid (ACA), was identified to interrupt AP2M1-virus interaction and exhibit potent antiviral efficacy against a number of viruses in vitro and in vivo, including the influenza A viruses (IAVs), Zika virus (ZIKV), human immunodeficiency virus, and coronaviruses including MERS-CoV and SARS-CoV-2. YxxØ mutation, AP2M1 depletion, or disruption by ACA causes incorrect localization of viral proteins, which is exemplified by the failure of nuclear import of IAV nucleoprotein and diminished endoplasmic reticulum localization of ZIKV-NS3 and enterovirus-A71-2C proteins, thereby suppressing viral replication. Our study reveals an evolutionarily conserved mechanism of protein-protein interaction between host and virus that can serve as a broad-spectrum antiviral target.


id: cord-310780-0k8owwf8
title: Relevance of signaling molecules for apoptosis induction on influenza A virus replication
author: Iwai, Atsushi
date: 2013-11-22
url: https://api.elsevier.com/content/article/pii/S0006291X13017816
doi: 10.1016/j.bbrc.2013.10.100
abstract:
  Abstract Apoptosis is an important mechanism to maintain homeostasis in mammals, and disruption of the apoptosis regulation mechanism triggers a range of diseases, such as cancer, autoimmune diseases, and developmental disorders. The severity of influenza A virus (IAV) infection is also closely related to dysfunction of apoptosis regulation. In the virus infected cells, the functions of various host cellular molecules involved in regulation of induction of apoptosis are modulated by IAV proteins to enable effective virus replication. The modulation of the intracellular signaling pathway inducing apoptosis by the IAV infection also affects extracellular mechanisms controlling apoptosis, and triggers abnormal host responses related to the disease severity of IAV infections. This review focuses on apoptosis related molecules involved in IAV replication and pathogenicity, the strategy of the virus propagation through the regulation of apoptosis is also discussed.


id: cord-314825-fzba05wn
author: Chauhan, Ravendra P.
date: 2020-05-08
txt: ./txt/cord-314825-fzba05wn.txt
cache: ./cache/cord-314825-fzba05wn.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32397138/
doi: 10.3390/pathogens9050355
title:
  A Systematic Review Analyzing the Prevalence and Circulation of Influenza Viruses in Swine Population Worldwide

abstract:
  The global anxiety and a significant threat to public health due to the current COVID-19 pandemic reiterate the need for active surveillance for the zoonotic virus diseases of pandemic potential. Influenza virus due to its wide host range and zoonotic potential poses such a significant threat to public health. Swine serve as a “mixing vessel” for influenza virus reassortment and evolution which as a result may facilitate the emergence of new strains or subtypes of zoonotic potential. In this context, the currently available scientific data hold a high significance to unravel influenza virus epidemiology and evolution. With this objective, the current systematic review summarizes the original research articles and case reports of all the four types of influenza viruses reported in swine populations worldwide. A total of 281 articles were found eligible through screening of PubMed and Google Scholar databases and hence were included in this systematic review. The highest number of research articles (n = 107) were reported from Asia, followed by Americas (n = 97), Europe (n = 55), Africa (n = 18), and Australia (n = 4). The H1N1, H1N2, H3N2, and A(H1N1)pdm09 viruses were the most common influenza A virus subtypes reported in swine in most countries across the globe, however, few strains of influenza B, C, and D viruses were also reported in certain countries. Multiple reports of the avian influenza virus strains documented in the last two decades in swine in China, the United States, Canada, South Korea, Nigeria, and Egypt provided the evidence of interspecies transmission of influenza viruses from birds to swine. Inter-species transmission of equine influenza virus H3N8 from horse to swine in China expanded the genetic diversity of swine influenza viruses. Additionally, numerous reports of the double and triple-reassortant strains which emerged due to reassortments among avian, human, and swine strains within swine further increased the genetic diversity of swine influenza viruses. These findings are alarming hence active surveillance should be in place to prevent future influenza pandemics.


id: cord-321112-w7x1dkds
title: IFITM Genes, Variants, and Their Roles in the Control and Pathogenesis of Viral Infections
author: Zhao, Xuesen
date: 2019-01-08
url: https://doi.org/10.3389/fmicb.2018.03228
doi: 10.3389/fmicb.2018.03228
abstract:
  Interferon-induced transmembrane proteins (IFITMs) are a family of small proteins that localize in the plasma and endolysosomal membranes. IFITMs not only inhibit viral entry into host cells by interrupting the membrane fusion between viral envelope and cellular membranes, but also reduce the production of infectious virions or infectivity of progeny virions. Not surprisingly, some viruses can evade the restriction of IFITMs and even hijack the antiviral proteins to facilitate their infectious entry into host cells or promote the assembly of virions, presumably by modulating membrane fusion. Similar to many other host defense genes that evolve under the selective pressure of microorganism infection, IFITM genes evolved in an accelerated speed in vertebrates and many single-nucleotide polymorphisms (SNPs) have been identified in the human population, some of which have been associated with severity and prognosis of viral infection (e.g., influenza A virus). Here, we review the function and potential impact of genetic variation for IFITM restriction of viral infections. Continuing research efforts are required to decipher the molecular mechanism underlying the complicated interaction among IFITMs and viruses in an effort to determine their pathobiological roles in the context of viral infections in vivo.


id: cord-321673-v5o49ees
title: Relevance of Viroporin Ion Channel Activity on Viral Replication and Pathogenesis
author: Nieto-Torres, Jose L.
date: 2015-07-03
url: https://www.ncbi.nlm.nih.gov/pubmed/26151305/
doi: 10.3390/v7072786
abstract:
  Modification of host-cell ionic content is a significant issue for viruses, as several viral proteins displaying ion channel activity, named viroporins, have been identified. Viroporins interact with different cellular membranes and self-assemble forming ion conductive pores. In general, these channels display mild ion selectivity, and, eventually, membrane lipids play key structural and functional roles in the pore. Viroporins stimulate virus production through different mechanisms, and ion channel conductivity has been proved particularly relevant in several cases. Key stages of the viral cycle such as virus uncoating, transport and maturation are ion-influenced processes in many viral species. Besides boosting virus propagation, viroporins have also been associated with pathogenesis. Linking pathogenesis either to the ion conductivity or to other functions of viroporins has been elusive for a long time. This article summarizes novel pathways leading to disease stimulated by viroporin ion conduction, such as inflammasome driven immunopathology.


id: cord-322933-5xnxjqm5
title: Collectins: Innate Immune Pattern Recognition Molecules
author: Murugaiah, Valarmathy
date: 2020-03-10
url: https://doi.org/10.1007/978-981-15-1580-4_4
doi: 10.1007/978-981-15-1580-4_4
abstract:
  Collectins are collagen-containing C-type (calcium-dependent) lectins which are important pathogen pattern recognising innate immune molecules. Their primary structure is characterised by an N-terminal, triple-helical collagenous region made up of Gly-X-Y repeats, an a-helical coiled-coil trimerising neck region, and a C-terminal C-type lectin or carbohydrate recognition domain (CRD). Further oligomerisation of this primary structure can give rise to more complex and multimeric structures that can be seen under electron microscope. Collectins can be found in serum as well as in a range of tissues at the mucosal surfaces. Mannanbinding lectin can activate the complement system while other members of the collectin family are extremely versatile in recognising a diverse range of pathogens via their CRDs and bring about effector functions designed at the clearance of invading pathogens. These mechanisms include opsonisation, enhancement of phagocytosis, triggering superoxidative burst and nitric oxide production. Collectins can also potentiate the adaptive immune response via antigen presenting cells such as macrophages and dendritic cells through modulation of cytokines and chemokines, thus they can act as a link between innate and adaptive immunity. This chapter describes the structure-function relationships of collectins, their diverse functions, and their interaction with viruses, bacteria, fungi and parasites.


id: cord-324696-htx0ul4o
title: Avian and human influenza virus compatible sialic acid receptors in little brown bats
author: Chothe, Shubhada K.
date: 2017-04-06
url: https://doi.org/10.1038/s41598-017-00793-6
doi: 10.1038/s41598-017-00793-6
abstract:
  Influenza A viruses (IAVs) continue to threaten animal and human health globally. Bats are asymptomatic reservoirs for many zoonotic viruses. Recent reports of two novel IAVs in fruit bats and serological evidence of avian influenza virus (AIV) H9 infection in frugivorous bats raise questions about the role of bats in IAV epidemiology. IAVs bind to sialic acid (SA) receptors on host cells, and it is widely believed that hosts expressing both SA α2,3-Gal and SA α2,6-Gal receptors could facilitate genetic reassortment of avian and human IAVs. We found abundant co-expression of both avian (SA α2,3-Gal) and human (SA α2,6-Gal) type SA receptors in little brown bats (LBBs) that were compatible with avian and human IAV binding. This first ever study of IAV receptors in a bat species suggest that LBBs, a widely-distributed bat species in North America, could potentially be co-infected with avian and human IAVs, facilitating the emergence of zoonotic strains.


id: cord-325192-italbsed
author: Desai, Tanay M.
date: 2014-04-03
url: https://www.ncbi.nlm.nih.gov/pubmed/24699674/
doi: 10.1371/journal.ppat.1004048
title:
  IFITM3 Restricts Influenza A Virus Entry by Blocking the Formation of Fusion Pores following Virus-Endosome Hemifusion

abstract:
  Interferon-induced transmembrane proteins (IFITMs) inhibit infection of diverse enveloped viruses, including the influenza A virus (IAV) which is thought to enter from late endosomes. Recent evidence suggests that IFITMs block virus hemifusion (lipid mixing in the absence of viral content release) by altering the properties of cell membranes. Consistent with this mechanism, excess cholesterol in late endosomes of IFITM-expressing cells has been reported to inhibit IAV entry. Here, we examined IAV restriction by IFITM3 protein using direct virus-cell fusion assay and single virus imaging in live cells. IFITM3 over-expression did not inhibit lipid mixing, but abrogated the release of viral content into the cytoplasm. Although late endosomes of IFITM3-expressing cells accumulated cholesterol, other interventions leading to aberrantly high levels of this lipid did not inhibit virus fusion. These results imply that excess cholesterol in late endosomes is not the mechanism by which IFITM3 inhibits the transition from hemifusion to full fusion. The IFITM3's ability to block fusion pore formation at a post-hemifusion stage shows that this protein stabilizes the cytoplasmic leaflet of endosomal membranes without adversely affecting the lumenal leaflet. We propose that IFITM3 interferes with pore formation either directly, through partitioning into the cytoplasmic leaflet of a hemifusion intermediate, or indirectly, by modulating the lipid/protein composition of this leaflet. Alternatively, IFITM3 may redirect IAV fusion to a non-productive pathway, perhaps by promoting fusion with intralumenal vesicles within multivesicular bodies/late endosomes.


id: cord-329680-ekxsv91t
author: Yu, Yunjia
date: 2019-12-23
url: https://www.ncbi.nlm.nih.gov/pubmed/31870450/
doi: 10.1186/s12985-019-1266-x
title:
  Inhibition effects of patchouli alcohol against influenza a virus through targeting cellular PI3K/Akt and ERK/MAPK signaling pathways

abstract:
  BACKGROUND: Patchouli alcohol (PA) is a tricyclic sesquiterpene extracted from Pogostemonis Herba, which is a traditional Chinese medicine used for therapy of inflammatory diseases. Recent studies have shown that PA has various pharmacological activities, including anti-bacterial and anti-viral effects. METHODS: In this study, the anti-influenza virus (IAV) activities and mechanisms were investigated both in vitro and in vivo. The inhibitory effects of PA against IAV in vitro were evaluated by plaque assay and immunofluorescence assay. The neuraminidase inhibition assay, hemagglutination inhibition (HI) assay, and western blot assay were used to explore the anti-viral mechanisms. The anti-IAV activities in vivo were determined by mice pneumonia model and HE staining. RESULTS: The results showed that PA significantly inhibited different IAV strains multiplication in vitro, and may block IAV infection through inactivating virus particles directly and interfering with some early stages after virus adsorption. Cellular PI3K/Akt and ERK/MAPK signaling pathways may be involved in the anti-IAV actions of PA. Intranasal administration of PA markedly improved mice survival and attenuated pneumonia symptoms in IAV infected mice, comparable to the effects of Oseltamivir. CONCLUSIONS: Therefore, Patchouli alcohol has the potential to be developed into a novel anti-IAV agent in the future.


id: cord-332725-2oc1yrzx
title: Nrf2 protects human alveolar epithelial cells against injury induced by influenza A virus
author: Kosmider, Beata
date: 2012-06-06
url: https://www.ncbi.nlm.nih.gov/pubmed/22672594/
doi: 10.1186/1465-9921-13-43
abstract:
  BACKGROUND: Influenza A virus (IAV) infection primarily targets respiratory epithelial cells and produces clinical outcomes ranging from mild upper respiratory infection to severe pneumonia. Recent studies have shown the importance of lung antioxidant defense systems against injury by IAV. Nuclear factor-erythroid 2 related factor 2 (Nrf2) activates the majority of antioxidant genes. METHODS: Alveolar type II (ATII) cells and alveolar macrophages (AM) were isolated from human lungs not suitable for transplantation and donated for medical research. In some studies ATII cells were transdifferentiated to alveolar type I-like (ATI-like) cells. Alveolar epithelial cells were infected with A/PR/8/34 (PR8) virus. We analyzed PR8 virus production, influenza A nucleoprotein levels, ROS generation and expression of antiviral genes. Immunocytofluorescence was used to determine Nrf2 translocation and western blotting to detect Nrf2, HO-1 and caspase 1 and 3 cleavage. We also analyzed ingestion of PR8 virus infected apoptotic ATII cells by AM, cytokine levels by ELISA, glutathione levels, necrosis and apoptosis by TUNEL assay. Moreover, we determined the critical importance of Nrf2 using adenovirus Nrf2 (AdNrf2) or Nrf2 siRNA to overexpress or knockdown Nrf2, respectively. RESULTS: We found that IAV induced oxidative stress, cytotoxicity and apoptosis in ATI-like and ATII cells. We also found that AM can ingest PR8 virus-induced apoptotic ATII cells (efferocytosis) but not viable cells, whereas ATII cells did not ingest these apoptotic cells. PR8 virus increased ROS production, Nrf2, HO-1, Mx1 and OAS1 expression and Nrf2 translocation to the nucleus. Nrf2 knockdown with siRNA sensitized ATI-like cells and ATII cells to injury induced by IAV and overexpression of Nrf2 with AdNrf2 protected these cells. Furthermore, Nrf2 overexpression followed by infection with PR8 virus decreased virus replication, influenza A nucleoprotein expression, antiviral response and oxidative stress. However, AdNrf2 did not increase IFN-λ1 (IL-29) levels. CONCLUSIONS: Our results indicate that IAV induces alveolar epithelial injury and that Nrf2 protects these cells from the cytopathic effects of IAV likely by increasing the expression of antioxidant genes. Identifying the pathways involved in protecting cells from injury during influenza infection may be particularly important for developing new therapeutic strategies.


id: cord-333655-lylt7qld
title: Bitter‐sweet symphony: glycan–lectin interactions in virus biology
author: Van Breedam, Wander
date: 2013-12-06
txt: ./txt/cord-333655-lylt7qld.txt
cache: ./cache/cord-333655-lylt7qld.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/24188132/
doi: 10.1111/1574-6976.12052
summary:
  In sum, it appears that the dimeric lectin galectin-1 can enhance HIV-1 infection efficiency by cross-linking viral and host cell glycans and thereby promoting firmer adhesion of the virus to the target cell surface and facilitating virus-receptor interactions (Ouellet et al., 2005; Mercier et al., 2008; St-Pierre et al., 2011; Sato et al., 2012) . As has been shown for IAV, acquisition or deletion of glycosylation sites may affect crucial steps in the viral infection/replication process (e.g. receptor binding, fusion, release of newly formed virions) (Ohuchi et al., 1997; Wagner et al., 2000; Tsuchiya et al., 2002; Kim & Park, 2012) , alter the capacity of the virus to avoid induction of/recognition by virus-specific antibodies (glycan shielding) Wei et al., 2010; Wanzeck et al., 2011; Kim & Park, 2012; Job et al., 2013; Sun et al., 2013) , and modulate viral interaction with various immune system lectins (Reading et al., 2007; Vigerust et al., 2007; Reading et al., 2009; Tate et al., 2011a, b) .

abstract:
  Glycans are carbohydrate modifications typically found on proteins or lipids, and can act as ligands for glycan‐binding proteins called lectins. Glycans and lectins play crucial roles in the function of cells and organs, and in the immune system of animals and humans. Viral pathogens use glycans and lectins that are encoded by their own or the host genome for their replication and spread. Recent advances in glycobiological research indicate that glycans and lectins mediate key interactions at the virus‐host interface, controlling viral spread and/or activation of the immune system. This review reflects on glycan–lectin interactions in the context of viral infection and antiviral immunity. A short introduction illustrates the nature of glycans and lectins, and conveys the basic principles of their interactions. Subsequently, examples are discussed highlighting specific glycan–lectin interactions and how they affect the progress of viral infections, either benefiting the host or the virus. Moreover, glycan and lectin variability and their potential biological consequences are discussed. Finally, the review outlines how recent advances in the glycan–lectin field might be transformed into promising new approaches to antiviral therapy.


id: cord-335871-zieuc7vk
author: Brazee, Patricia L.
date: 2020-05-13
url: https://api.elsevier.com/content/article/pii/S0300289620301381
doi: 10.1016/j.arbres.2020.04.019
title:
  Targeting the Linear Ubiquitin Assembly Complex to Modulate the Host Response and Improve Influenza A Virus Induced Lung Injury

abstract:
  Abstract Influenza virus infection is characterized by symptoms ranging from mild congestion and body aches to severe pulmonary edema and respiratory failure. While the majority of those exposed have minor symptoms and recover with little morbidity, an estimated 500,000 people succumb to IAV-related complications each year worldwide. In these severe cases, an exaggerated inflammatory response, known as “cytokine storm”, occurs which results in damage to the respiratory epithelial barrier and development of acute respiratory distress syndrome (ARDS). Data from retrospective human studies as well as experimental animal models of influenza virus infection highlight the fine line between an excessive and an inadequate immune response, where the host response must balance viral clearance with exuberant inflammation. Current pharmacological modulators of inflammation, including corticosteroids and statins, have not been successful in improving outcomes during influenza virus infection. We have reported that the amplitude of the inflammatory response is regulated by Linear Ubiquitin Assembly Complex (LUBAC) activity and that dampening of LUBAC activity is protective during severe influenza virus infection. Therapeutic modulation of LUBAC activity may be crucial to improve outcomes during severe influenza virus infection, as it functions as a molecular rheostat of the host response. Here we review the evidence for modulating inflammation to ameliorate influenza virus infection-induced lung injury, data on current anti-inflammatory strategies, and potential new avenues to target viral inflammation and improve outcomes.


id: cord-338070-y8zi8iz9
author: Liu, Wei
date: 2020-08-31
url: https://doi.org/10.1007/s10096-020-04020-5
doi: 10.1007/s10096-020-04020-5
title:
  Pharmacological inhibition of poly (ADP-ribose) polymerase by olaparib ameliorates influenza-virus-induced pneumonia in mice

abstract:
  Treatments against influenza A viruses (IAV) have to be updated regularly due to antigenic drift and drug resistance. Poly (ADP-ribose) polymerases (PARPs) are considered effective therapeutic targets of acute lung inflammatory injury. This study aimed to explore the effects of PARP-1 inhibitor olaparib on IAV-induced lung injury and the underlying mechanisms. Male wild-type C57BL/6 mice were intranasally infected with IAV strain H1N1 to mimic pneumonia experimentally. Olaparib at different doses was intraperitoneally injected 2 days before and 5 consecutive days after virus stimulation. On day 6 post-infection, lung tissues as well as bronchoalveolar lavage fluid (BALF) were sampled for histological and biochemical analyses. Olaparib increased the survival rate of IAV mice dose-dependently. Olaparib remarkably reduced IAV mRNA expression, myeloperoxidase (MPO) level, and inflammatory cell infiltration in IAV lungs. Moreover, olaparib significantly reduced the level of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-6, and IL-4 and increased IL-10 in IAV lungs. Also, olaparib efficiently reduced IL-6, monocyte chemotactic protein (MCP)-1, granulocyte colony-stimulating factor (G-CSF), TNF-α, chemokine (C–X–C motif) ligand (CXCL)1, CXCL10, chemokine (C–C motif) ligand (CCL)3, and regulated on activation, normal T cell expressed and secreted (RANTES) release in IAV BALF. Olaparib decreased PARylated protein content and p65, IκBα phosphorylation in IAV lung tissues. This study successfully constructed the pneumonia murine model using IAV. Olaparib decreased IAV-induced mortality in mice, lung injury, and cytokine production possibly via modulation of PARP-1/NF-κB axis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10096-020-04020-5) contains supplementary material, which is available to authorized users.


id: cord-339392-2ocz784l
title: Influenza A Virus Nucleoprotein Exploits Hsp40 to Inhibit PKR Activation
author: Sharma, Kulbhushan
date: 2011-06-15
txt: ./txt/cord-339392-2ocz784l.txt
cache: ./cache/cord-339392-2ocz784l.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1371/journal.pone.0020215
doi: 10.1371/journal.pone.0020215
summary:
  BACKGROUND: Double-stranded RNA dependent protein kinase (PKR) is a key regulator of the anti-viral innate immune response in mammalian cells. In case of influenza A virus (IAV) infection, P58(IPK) is known to dissociate from Hsp40 and inhibit PKR activation. PRINCIPAL FINDINGS: Human heat shock 40 protein (Hsp40) was identified as an interacting partner of Influenza A virus nucleoprotein (IAV NP) using a yeast two-hybrid screen. It is known that under stress conditions the expression level of Hsp40 is enhanced and its cellular localization changes from cytoplasmic to nuclear [38] , however its distribution in influenza virus infected cells was not studied. Taken together, these results suggest that during IAV infection, NP induces the dissociation of the P58 IPK -Hsp40 complex leading to an inhibition of PKR activation and downregulation of eIF2a phosphorylation. In case of influenza virus infection, viral NS1 protein is known to bind directly to PKR and inhibit its activation [20, 21] .

abstract:
  BACKGROUND: Double-stranded RNA dependent protein kinase (PKR) is a key regulator of the anti-viral innate immune response in mammalian cells. PKR activity is regulated by a 58 kilo Dalton cellular inhibitor (P58(IPK)), which is present in inactive state as a complex with Hsp40 under normal conditions. In case of influenza A virus (IAV) infection, P58(IPK) is known to dissociate from Hsp40 and inhibit PKR activation. However the influenza virus component responsible for PKR inhibition through P58(IPK) activation was hitherto unknown. PRINCIPAL FINDINGS: Human heat shock 40 protein (Hsp40) was identified as an interacting partner of Influenza A virus nucleoprotein (IAV NP) using a yeast two-hybrid screen. This interaction was confirmed by co-immunoprecipitation studies from mammalian cells transfected with IAV NP expressing plasmid. Further, the IAV NP-Hsp40 interaction was validated in mammalian cells infected with various seasonal and pandemic strains of influenza viruses. Cellular localization studies showed that NP and Hsp40 co-localize primarily in the nucleus. During IAV infection in mammalian cells, expression of NP coincided with the dissociation of P58(IPK) from Hsp40 and decrease PKR phosphorylation. We observed that, plasmid based expression of NP in mammalian cells leads to decrease in PKR phosphorylation. Furthermore, inhibition of NP expression during influenza virus replication led to PKR activation and concomitant increase in eIF2α phosphorylation. Inhibition of NP expression also led to reduced IRF3 phosphorylation, enhanced IFN β production and concomitant reduction of virus replication. Taken together our data suggest that NP is the viral factor responsible for P58(IPK) activation and subsequent inhibition of PKR-mediated host response during IAV infection. SIGNIFICANCE: Our findings demonstrate a novel role of IAV NP in inhibiting PKR-mediated anti-viral host response and help us understand P58(IPK) mediated inhibition of PKR activity during IAV infection.


id: cord-342691-8jcfzexy
title: Consensus transcriptional regulatory networks of coronavirus-infected human cells
author: Ochsner, Scott A.
date: 2020-09-22
url: https://www.ncbi.nlm.nih.gov/pubmed/32963239/
doi: 10.1038/s41597-020-00628-6
abstract:
  Establishing consensus around the transcriptional interface between coronavirus (CoV) infection and human cellular signaling pathways can catalyze the development of novel anti-CoV therapeutics. Here, we used publicly archived transcriptomic datasets to compute consensus regulatory signatures, or consensomes, that rank human genes based on their rates of differential expression in MERS-CoV (MERS), SARS-CoV-1 (SARS1) and SARS-CoV-2 (SARS2)-infected cells. Validating the CoV consensomes, we show that high confidence transcriptional targets (HCTs) of MERS, SARS1 and SARS2 infection intersect with HCTs of signaling pathway nodes with known roles in CoV infection. Among a series of novel use cases, we gather evidence for hypotheses that SARS2 infection efficiently represses E2F family HCTs encoding key drivers of DNA replication and the cell cycle; that progesterone receptor signaling antagonizes SARS2-induced inflammatory signaling in the airway epithelium; and that SARS2 HCTs are enriched for genes involved in epithelial to mesenchymal transition. The CoV infection consensomes and HCT intersection analyses are freely accessible through the Signaling Pathways Project knowledgebase, and as Cytoscape-style networks in the Network Data Exchange repository.


id: cord-344093-3bniy5b5
author: Peteranderl, Christin
date: 2017-03-22
url: https://doi.org/10.3389/fimmu.2017.00313
doi: 10.3389/fimmu.2017.00313
title:
  The Impact of the Interferon/TNF-Related Apoptosis-Inducing Ligand Signaling Axis on Disease Progression in Respiratory Viral Infection and Beyond

abstract:
  Interferons (IFNs) are well described to be rapidly induced upon pathogen-associated pattern recognition. After binding to their respective IFN receptors and activation of the cellular JAK/signal transducer and activator of transcription signaling cascade, they stimulate the transcription of a plethora of IFN-stimulated genes (ISGs) in infected as well as bystander cells such as the non-infected epithelium and cells of the immune system. ISGs may directly act on the invading pathogen or can either positively or negatively regulate the innate and adaptive immune response. However, IFNs and ISGs do not only play a key role in the limitation of pathogen spread but have also been recently found to provoke an unbalanced, overshooting inflammatory response causing tissue injury and hampering repair processes. A prominent regulator of disease outcome, especially in—but not limited to—respiratory viral infection, is the IFN-dependent mediator TRAIL (TNF-related apoptosis-inducing ligand) produced by several cell types including immune cells such as macrophages or T cells. First described as an apoptosis-inducing agent in transformed cells, it is now also well established to rapidly evoke cellular stress pathways in epithelial cells, finally leading to caspase-dependent or -independent cell death. Hereby, pathogen spread is limited; however in some cases, also the surrounding tissue is severely harmed, thus augmenting disease severity. Interestingly, the lack of a strictly controlled and well balanced IFN/TRAIL signaling response has not only been implicated in viral infection but might furthermore be an important determinant of disease progression in bacterial superinfections and in chronic respiratory illness. Conclusively, the IFN/TRAIL signaling axis is subjected to a complex modulation and might be exploited for the evaluation of new therapeutic concepts aiming at attenuation of tissue injury.


id: cord-347053-m5m4zgfy
title: Host–Pathogen Responses to Pandemic Influenza H1N1pdm09 in a Human Respiratory Airway Model
author: Pharo, Elizabeth A.
date: 2020-06-24
url: https://www.ncbi.nlm.nih.gov/pubmed/32599823/
doi: 10.3390/v12060679
abstract:
  The respiratory Influenza A Viruses (IAVs) and emerging zoonotic viruses such as Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) pose a significant threat to human health. To accelerate our understanding of the host–pathogen response to respiratory viruses, the use of more complex in vitro systems such as normal human bronchial epithelial (NHBE) cell culture models has gained prominence as an alternative to animal models. NHBE cells were differentiated under air-liquid interface (ALI) conditions to form an in vitro pseudostratified epithelium. The responses of well-differentiated (wd) NHBE cells were examined following infection with the 2009 pandemic Influenza A/H1N1pdm09 strain or following challenge with the dsRNA mimic, poly(I:C). At 30 h postinfection with H1N1pdm09, the integrity of the airway epithelium was severely impaired and apical junction complex damage was exhibited by the disassembly of zona occludens-1 (ZO-1) from the cell cytoskeleton. wdNHBE cells produced an innate immune response to IAV-infection with increased transcription of pro- and anti-inflammatory cytokines and chemokines and the antiviral viperin but reduced expression of the mucin-encoding MUC5B, which may impair mucociliary clearance. Poly(I:C) produced similar responses to IAV, with the exception of MUC5B expression which was more than 3-fold higher than for control cells. This study demonstrates that wdNHBE cells are an appropriate ex-vivo model system to investigate the pathogenesis of respiratory viruses.


id: cord-347304-1o4fb3na
title: miR‐193b represses influenza A virus infection by inhibiting Wnt/β‐catenin signalling
author: Yang, Xiaoyun
date: 2019-01-25
txt: ./txt/cord-347304-1o4fb3na.txt
cache: ./cache/cord-347304-1o4fb3na.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1111/cmi.13001
doi: 10.1111/cmi.13001
summary:
  Overexpression of four selected miRNAs (miR‐193b, miR‐548f‐1, miR‐1‐1, and miR‐509‐1) that down‐regulated the Wnt/β‐catenin signalling pathway reduced viral mRNA, protein levels in A/PR/8/34‐infected HEK293 cells, and progeny virus production. Because miR-193b showed greater inhibition of Wnt/β-catenin signalling than miR-193a, we tested the anti-IAV activities of miR-193b and the other miRNAs. We overexpressed each miRNA in HEK293 cells for 24 hr, infected the cells with A/PR/8/34 at a multiplicity of infection (MOI) of 0.01 for 48 hr, and determined viral mRNA and protein expression in infected cells and the titre in the culture medium. It is noteworthy that miR-509-1 inhibited the Wnt/β-catenin signalling, the second most but merely showed moderate suppression of the IAV infection, suggesting a possible offtarget effect of the miRNA. Furthermore, four miRNAs (miR-193b, miR-548f-1, miR-1-1, and miR-509-1) that down-regulated the Wnt/β-catenin signalling pathway were shown to suppress IAV replication and virus production.

abstract:
  Due to an increasing emergence of new and drug‐resistant strains of the influenza A virus (IAV), developing novel measures to combat influenza is necessary. We have previously shown that inhibiting Wnt/β‐catenin pathway reduces IAV infection. In this study, we aimed to identify antiviral human microRNAs (miRNAs) that target the Wnt/β‐catenin signalling pathway. Using a miRNA expression library, we identified 85 miRNAs that up‐regulated and 20 miRNAs that down‐regulated the Wnt/β‐catenin signalling pathway. Fifteen miRNAs were validated to up‐regulate and five miRNAs to down‐regulate the pathway. Overexpression of four selected miRNAs (miR‐193b, miR‐548f‐1, miR‐1‐1, and miR‐509‐1) that down‐regulated the Wnt/β‐catenin signalling pathway reduced viral mRNA, protein levels in A/PR/8/34‐infected HEK293 cells, and progeny virus production. Overexpression of miR‐193b in lung epithelial A549 cells also resulted in decreases of A/PR/8/34 infection. Furthermore, miR‐193b inhibited the replication of various strains, including H1N1 (A/PR/8/34, A/WSN/33, A/Oklahoma/3052/09) and H3N2 (A/Oklahoma/309/2006), as determined by a viral reporter luciferase assay. Further studies revealed that β‐catenin was a target of miR‐193b, and β‐catenin rescued miR‐193b‐mediated suppression of IAV infection. miR‐193b induced G0/G1 cell cycle arrest and delayed vRNP nuclear import. Finally, adenovirus‐mediated gene transfer of miR‐193b to the lung reduced viral load in mice challenged by a sublethal dose of A/PR/8/34. Collectively, our findings suggest that miR‐193b represses IAV infection by inhibiting Wnt/β‐catenin signalling.


id: cord-355931-3mvmetuv
title: Spiky nanostructures for virus inhibition and infection prevention
author: Nie, Chuanxiong
date: 2020-07-16
url: https://api.elsevier.com/content/article/pii/S2590183420300107
doi: 10.1016/j.smaim.2020.07.004
abstract:
  Abstract The outbreak of a novel highly infectious virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has aroused people’s concern about public health. The lack of ready-to-use vaccines and therapeutics makes the fight with these pathogens extremely difficult. To this point, rationally designed virus entry inhibitors that block the viral interaction with its receptor can be novel strategies to prevent virus infection. For ideal inhibition of the virus, the virus-inhibitor interaction has to outperform the virus-host interaction. In our view, the morphology of the inhibitor should be carefully designed to benefit virus-inhibitor binding, especially that the surfaces of viruses are mostly rough due to the existence of surface proteins for receptor-binding. In this perspective article, we would like to discuss the recent progress of designing inhibitors with spiky topography to maximize the interactions between viruses and inhibitors. We also would like to share our idea for the future study of inhibitors to prevent virus infection.


