# ent

id: cord-002164-oqc9h2lu
type: DNA
entity:
  Viral Genome date 2016 08 09 journal Front Hum Neurosci DOI 10 3389 fnhum 2016 00403 sha a65111e0e1a8f26d4789ea6439cae1cfa5b391b8 doc_id 2164 cord_uid oqc9h2lu


id: cord-003187-qdbcdn2j
type: DISEASE
entity:
  influenza A virus polymerase Biochemical evaluation of the inhibition properties of favipiravir and 2 C methyl cytidine triphosphates


id: cord-003403-ypefqm71
type: ORG
entity:
  Collaborative Study to Evaluate a Candidate World Health Organization International Standard for Zika Virus


id: cord-002581-r7mskri0
type: ORG
entity:
  Microcephaly Brazil Interim Guidelines for the Evaluation and Testing of Infants with Possible Congenital Zika Virus Infection United States Interim Guidelines for Pregnant Women During a Zika Virus Outbreak United States Human


id: cord-002581-r7mskri0
type: CHEMICAL
entity:
  Nieto Lucas Avelino Silva Vivian I Trindade Mateus Nogueira Juliana Oliveira Consuelo S Maestri Alvino Felix Alvina


id: cord-002581-r7mskri0
type: DISEASE
entity:
  somatic mutations Class switch recombination and somatic hypermutation of virus neutralizing antibodies


id: cord-003453-p2buyrcj
type: DNA
entity:
  human cytomegalovirus HCMV 10 herpes simplex virus HSV 11 influenza virus 12 Chikungunya virus CHIKV


id: cord-009399-6zpkpdzu
type: GGP
entity:
  interferon inducible transmembrane proteins Human interferon induced transmembrane protein 1 2 3 IFITM1 2 3


id: cord-004053-nmt221tu
type: WORK_OF_ART
entity:
  A Language and Environment for Statistical Computing R Foundation for Statistical Computing Zika Virus


id: cord-004053-nmt221tu
type: WORK_OF_ART
entity:
  The Flavivirus Precursor Membrane Envelope Protein Complex Structure and Maturation Fighting Cancer with Viruses Oncolytic Virus Therapy


id: cord-016796-g4kqqpy1
type: ORG
entity:
  Advanced Immunotechnological Methods for Detection and Diagnosis of Viral Infections Current Applications and Future Challenges


id: cord-102279-ena1usqv
type: GGP
entity:
  bioRxiv DOI 10 1101 2020 05 12 091611 sha cd9a7050ec380e1f91413d80c5e6f8efd82d014c doc_id 102279 cord_uid ena1usqv The endoplasmic reticulum ER


id: cord-260336-kwzo8puo
type: ORG
entity:
  Shanghai Public Health Clinical Center Animal Welfare and Ethics Committee Institutional Laboratory Animal Care and Use Committee


id: cord-263868-ewnf96cz
type: CHEMICAL
entity:
  DMF 162 8 158 2 158 0 134 5 117 4 115 1 112 7 69 8 69 6 68 1 68 1 61 1 59 3 The pure maleimide biotin


id: cord-278286-1xk31726
type: PROTEIN
entity:
  anti rabbit mouse Alexa 568 488 647 conjugated goat antibodies Life Technologies 4 6 diamidino 2 phenylindole DAPI Life Technologies


id: cord-278286-1xk31726
type: DISEASE
entity:
  ZIKV infected Vero hOEC and mOEC cells Fig S2 were almost identical to those obtained for hCMEC D3 cells Fig 5 To examine the virus persistence


id: cord-273326-gmw8gl2r
type: PROTEIN
entity:
  interferon activating small molecule 1 2 fluorophenyl 2 5 isopropyl 1 3 4 thiadiazol 2 yl 1 2 ihydrochromeno 2 3 c pyrrole 3 9 dione AVC


id: cord-273326-gmw8gl2r
type: CHEMICAL
entity:
  1 2S butan 2 yl N 4 6 dimethyl 2 oxo 1H pyridin 3 yl methyl 3 methyl 6 6 piperazin 1 ylpyridin 3 yl indole 4 carboxamide GSK 126


id: cord-319781-6thdg2up
type: GGP
entity:
  Rev DOI 10 1016 j sxmr 2020 06 003 sha ed553038440e4874986451ca8d5e1832e8ef19fd doc_id 319781 cord_uid 6thdg2up


id: cord-319781-6thdg2up
type: DISEASE
entity:
  genitalia testis orchitis prostate reproductive semen sperm hormones endocrine luteinizing hormone folliclestimulating


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


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


id: cord-002341-v4r5d26a
type: DISEASE
entity:
  prostate male ovary uterus female kidney urinary bladder spleen liver pancreas intestine heart lung and salivary gland


id: cord-002341-v4r5d26a
type: DISEASE
entity:
  testis epididymis ovary uterus kidney spleen small intestine pancreas and salivary gland of the dexamethasone


id: cord-338136-nbtkl5cx
type: WORK_OF_ART
entity:
  Vital Signs Update on Zika Virus Associated Birth Defects and Evaluation of All U S Infants with Congenital Zika Virus Exposure U S Zika Pregnancy Registry Probable


id: cord-309275-soffxxqu
type: DISEASE
entity:
  human immunodeficiency virus HIV influenza A virus IAV human adenovirus HAdV severe acute respiratory syndrome coronavirus SARSC papillomavirus HPV respiratory syncytial virus RSV


id: cord-311007-0i1abjfa
type: DNA
entity:
  cDNA Clone date 2016 09 28 journal mSphere DOI 10 1128 msphere 00246 16 sha ca73d739c9c8c6ddb081d0badcea76f821ae147a doc_id 311007


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-290385-0smnl70i
type: PROTEIN
entity:
  lactate dehydrogenase aspartate aminotransferase g glutamyl transferase fibrinogen ferritin C reactive protein


id: cord-290385-0smnl70i
type: DISEASE
entity:
  coronaviruses severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus influenza viruses and Ebola virus 2e11


id: cord-294798-ji3p0l4j
type: ORG
entity:
  the Chikungunya Virus Caribbean Outbreak Reveals Novel Evolutionary Genomic Elements Emergence of Human Arboviral Diseases


id: cord-294798-ji3p0l4j
type: WORK_OF_ART
entity:
  Improving the Accuracy of Demographic and Molecular Clock Model Comparison While Accommodating Phylogenetic Uncertainty Zika


id: cord-326512-iex98lr1
type: PROTEIN
entity:
  anti human CD20 FITC Invitrogen Carlsbad CA IgG APC H7 CD3 Pacific Blue CD27 PerCP Cy5 5 BD Biosciences Franklin Lakes NJ


id: cord-015352-2d02eq3y
type: PROTEIN
entity:
  N Colavolpe A Aschero B Bourliere Najean C Roman F Khachab H Pico M Kheiri G Gorincour C Desvignes P Petit Marseille FR


id: cord-015352-2d02eq3y
type: PROTEIN
entity:
  Help E Kovacs 1 N Pinter 2 G Balázs 1 A Machovitsch 1 A Arany 1 Z Liptai 1 L Fonyad 1 P Benke 1 1 Budapest HU 2 Amherst US Objective


id: cord-015352-2d02eq3y
type: GGP
entity:
  CMD p 0 11 Linear hierarchical regressions controlling the age did not show a significant relation between ADC and cortical or renal transit times p 0 68 but lower FA values


id: cord-015352-2d02eq3y
type: DISEASE
entity:
  pulmonary artery pulmonary sequestration systemic arterialization of lung absence of inferior vena cava


id: cord-015352-2d02eq3y
type: DISEASE
entity:
  congenital pulmonary airway malformation CPAM 1 hemithorax pulmonary sequestration 1 hemithorax partial pneumothorax


id: cord-010119-t1x9gknd
type: CELL_LINE
entity:
  Pluripotent Stem Cell Derived Cardiomyocyte Toxicity By Supernatant of Long Term Stored Red Blood Cells


id: cord-010119-t1x9gknd
type: DNA
entity:
  RhD protein IVS1 29C rs2301153 IVS3 1 117C rs28521909 and IVS3 1 124A rs28562109 Two 15 4 were D1 and heterozygous


id: cord-010119-t1x9gknd
type: DNA
entity:
  RHD wildtype exon 9 mutant RHD c 1154G C mutant RHD c 1154 31C T and double RHD mutants c 1154G C plus c 1154 31C T


id: cord-010119-t1x9gknd
type: CELL_TYPE
entity:
  blood center RBC 2RBC PLT P PLT PLT RBC P PLT RBC 2PLT 2PLT RBC 2PLT P donations 47990 63 1775 10832 968 476 67 1150 142 10252 Citrate exposure mls 41 85 71 138 263 266 300 322 349 478 Study Design Method A randomized 2 1


id: cord-010119-t1x9gknd
type: CELL_TYPE
entity:
  ABO Rh Beckman Coulter PK System Blood Grouping and Phenotyping during the period 7 1 2008 4 1 2017 ABO


id: cord-010119-t1x9gknd
type: CELL_LINE
entity:
  Cell SaverV R HaemoneticsV R Braintree MA patients own blood shed during surgery is collected washed concentrated and reinfused lessening the need for transfusion support This study sought to examine the amount of allogeneic donor RBC


id: cord-010119-t1x9gknd
type: DNA
entity:
  ceJAL ceMO ceBI 7 0 7 0 7 0 Total 106 8 110 4 113 2 142A TRANSFUSION 2017 Vol 57 Supplement S3 reagents


id: cord-010119-t1x9gknd
type: CELL_LINE
entity:
  Immucor Gamma clone Series 4 and 5 and Quotient ALBAclone blend and alpha anti D Papain treated RBCs


id: cord-010119-t1x9gknd
type: PROTEIN
entity:
  anti Mur Brian Adkins 1 Princess Maynie 1 Carol Chandler 1 Shelia Garret 1 and Pampee Young 2 1 Vanderbilt 2


id: cord-010119-t1x9gknd
type: GGP
entity:
  gHb 7 6 6 0 3 a 5 2 6 0 3 7 3 6 0 2 a 5 5 6 0 3 7 3 6 0 4 a 4 9 6 0 5 Extracellular Lactate mM 5 6 1 a 6 6 1 7 6 0 8 6 0 6 6 0 6 6 1 Extracellular Glucose mM 32 6 1


id: cord-010119-t1x9gknd
type: GGP
entity:
  Impl periods 3 4 Table More severe reactions showed an increasing trend that only became significant in Post Impl periods 3 4


id: cord-010119-t1x9gknd
type: CL
entity:
  allogeneic blood donors and autologous donors which were intended to represent a hospitalized patient population to determine a mean and range of normal levels This 2 5 year retrospective study was performed to assess levels of RBC bound IgG IgA and IgM in normal donors Study Design Method Residual EDTA


id: cord-010119-t1x9gknd
type: ORG
entity:
  TPE Cytoreductive Therapy for Cellular Hyperviscosity Utility of Cytapheresis Treatment for Chronic Myelogenous Leukemia


id: cord-010119-t1x9gknd
type: ORG
entity:
  Washington University School of Medicine 3 Nationwide Children s Hospital Background Case Studies Transfusion


id: cord-010119-t1x9gknd
type: WORK_OF_ART
entity:
  Clinical Oral Abstract Session Novel Approaches to Processing and Assessing Cell Therapy Products A Paradigm Shift in Stem Cell Isolation and Storage Jeffrey Drew Cells4life Group LLP Background Case Studies Widespread


id: cord-010119-t1x9gknd
type: EVENT
entity:
  A Streamlined Mixed Lymphocyte Reaction MLR Assay for Evaluation of Human Mesenchymal Stem Cell Immunomodulation Activity Christopher P Delavan 1 Maryanne C Herzig 1


id: cord-010119-t1x9gknd
type: ORG
entity:
  US Army Institute of Surgical Research 2 U S Army Institute of Surgical Research Background Case Studies


id: cord-010119-t1x9gknd
type: WORK_OF_ART
entity:
  Using Genetic Markers to Select Responders and Non Responders Sickle Cell Disease SCD Patients for Transfusion with RH Haplotype Matching Red Blood


id: cord-010119-t1x9gknd
type: ORG
entity:
  Department of Pathology University of Colorado Anschutz Medical Campus 2 Department of Medicine Division of Hematology University of Colorado Hospital 3


id: cord-010119-t1x9gknd
type: ORG
entity:
  University of California San Francisco 4 Nationwide Children s Hospital 5 Academic Medical Center 6 Canadian Blood Services Background Case


id: cord-010119-t1x9gknd
type: ORG
entity:
  US Army Institute of Surgical Research 2 U S Army Institute of Surgical Research 3 University of Washington


id: cord-010119-t1x9gknd
type: ORG
entity:
  Red Cell Concentrate Volume and Manufacturing Method Impact Post Thaw Quality in Cryopreserved Products


id: cord-010119-t1x9gknd
type: ORG
entity:
  National University Hospital 3 National University Hospital Singapore Background Case Studies Plasma


id: cord-010119-t1x9gknd
type: ORG
entity:
  University of Texas Southwestern Medical Center 2 UT Southwestern Medical Center Background Case Studies


id: cord-010119-t1x9gknd
type: ORG
entity:
  mother s sisters Management of Severe Autoimmune Hemolytic Anemia A Case Report of an Infant Treated with Manual Whole Blood Exchange


id: cord-010119-t1x9gknd
type: PRODUCT
entity:
  anti e Automated Eluates Comparison of Solid Phase Red Cell Adherence and Gel Automated Eluate Testing Jayanna Slayten 1


id: cord-010119-t1x9gknd
type: ORG
entity:
  University Medical Center Department of Pathology Microbiology and Immunology Background Case Studies Antibody


id: cord-010119-t1x9gknd
type: ORG
entity:
  Graduate Institute of Clinical Medicine College of Medicine National Taiwan University 3 Division of Hepatogastroenterology Department of Internal Medicine


id: cord-010119-t1x9gknd
type: ORG
entity:
  the FDA Guidance entitled Revised Recommendations for Reducing the Risk of Zika Virus Transmission by Blood


id: cord-010119-t1x9gknd
type: ORG
entity:
  Microbiology Department Cerus Corporation 2 Scientific Affairs Department Cerus Corporation Background Case Studies


id: cord-010119-t1x9gknd
type: ORG
entity:
  Centers for Disease Control and Prevention National Health Insurance and Health Promotion Administration


id: cord-010119-t1x9gknd
type: WORK_OF_ART
entity:
  Transfusion Transmissible Infections Among Blood Donors and Strategy on Direct Laboratory Testing Cost of Blood Screening


id: cord-010119-t1x9gknd
type: ORG
entity:
  Federal State Regulations Inventory Structure Management Product Storage Testing Tracking Traceability Emergency Release Protocol


id: cord-010119-t1x9gknd
type: WORK_OF_ART
entity:
  Transfusion Service Workflow Comparison of Two High Volume High Throughput Analyzers Aaron Samson 1 Kimberly Monnin 1


id: cord-010119-t1x9gknd
type: WORK_OF_ART
entity:
  The Merging of Immunohematology Reference Lab s IRL Inventories Using Technology to Create Advanced Search


id: cord-010119-t1x9gknd
type: ORG
entity:
  Guidance for Industry Recommendations for Donor Screening Deferral and Product Management to Reduce the Risk of Transfusion Transmission of Zika Virus


id: cord-010119-t1x9gknd
type: CHEMICAL
entity:
  Cheryl Lobo 4 Michael Paul Busch 3 Susan L Stramer 2 and Jeffrey M Linnen 1 1 Grifols Diagnostic Solutions Inc 2 American Red Cross 3 Blood Systems Research Institute 4 New York Blood


# bib

id: cord-002164-oqc9h2lu
author: Kumar, Ashutosh
date: 2016-08-09
txt: ./txt/cord-002164-oqc9h2lu.txt
cache: ./cache/cord-002164-oqc9h2lu.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4977292/
doi: 10.3389/fnhum.2016.00403
summary:
  We, for this important reason, searched for the RARE consensus sequence (5 ′ -AGGTCA-3 ′ ) repeats in the genomic sequences of the ZIKV strains with a hypothesis that the virus might act through disruption of normal retinoic acid signaling mediated by incorporation of these sequences into the DNA of developing host brain cells. In view of (1) the bioinformatic evidence of the presence of RARE sequence repeats in genome sequences of ZIKV strains and in other viruses known to cause congenital brain malformation (Table 3) and (2) confirmed role of retinoic acid in neural tube formation and further brain development mediated through RARE sequences, it is scientifically coherent to assume that a RARE sequence dependent mechanism could be the underlying mechanism of microcephaly seen in ZIKV infected fetuses.

title:
  A Possible Mechanism of Zika Virus Associated Microcephaly: Imperative Role of Retinoic Acid Response Element (RARE) Consensus Sequence Repeats in the Viral Genome

abstract:
  Owing to the reports of microcephaly as a consistent outcome in the fetuses of pregnant women infected with ZIKV in Brazil, Zika virus (ZIKV)—microcephaly etiomechanistic relationship has recently been implicated. Researchers, however, are still struggling to establish an embryological basis for this interesting causal handcuff. The present study reveals robust evidence in favor of a plausible ZIKV-microcephaly cause-effect liaison. The rationale is based on: (1) sequence homology between ZIKV genome and the response element of an early neural tube developmental marker “retinoic acid” in human DNA and (2) comprehensive similarities between the details of brain defects in ZIKV-microcephaly and retinoic acid embryopathy. Retinoic acid is considered as the earliest factor for regulating anteroposterior axis of neural tube and positioning of structures in developing brain through retinoic acid response elements (RARE) consensus sequence (5′–AGGTCA–3′) in promoter regions of retinoic acid-dependent genes. We screened genomic sequences of already reported virulent ZIKV strains (including those linked to microcephaly) and other viruses available in National Institute of Health genetic sequence database (GenBank) for the RARE consensus repeats and obtained results strongly bolstering our hypothesis that ZIKV strains associated with microcephaly may act through precipitation of dysregulation in retinoic acid-dependent genes by introducing extra stretches of RARE consensus sequence repeats in the genome of developing brain cells. Additional support to our hypothesis comes from our findings that screening of other viruses for RARE consensus sequence repeats is positive only for those known to display neurotropism and cause fetal brain defects (for which maternal-fetal transmission during developing stage may be required). The numbers of RARE sequence repeats appeared to match with the virulence of screened positive viruses. Although, bioinformatic evidence and embryological features are in favor of our hypothesis, additional studies including animal models are warranted to validate our proposition. Such studies are likely to unfold ZIKV-microcephaly association and may help in devising methods to combat it.


id: cord-002247-e0z5ypii
title: Preparedness for Zika virus testing in the World Health Organization Western Pacific Region
author: Squires, Raynal C
date: 2016-03-31
txt: ./txt/cord-002247-e0z5ypii.txt
cache: ./cache/cord-002247-e0z5ypii.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052899/
doi: 10.5365/wpsar.2016.7.1.007
summary:
  On 1 February 2016, the World Health Organization (WHO) declared that clusters of microcephaly cases and other neurological disorders occurring in Zika virus (ZIKV)-affected areas constituted a public health emergency of international concern. The WHO Regional Office for the Western Pacific therefore initiated a rapid survey among national-level public health laboratories in 19 countries and areas to determine regional capacity for ZIKV detection. A total of 28 surveys to national-level laboratories likely to be tasked with ZIKV testing were distributed to 19 countries in the Region (omitting resource-limited countries with Zika virus testing preparedness in the Western Pacific Region Squires & Konings reporting having this capacity. While this survey reveals a broad availability of molecular diagnostics to support surveillance of ZIKV in the Western Pacific Region, further key roles remain for laboratories in helping to unravel the pathogenicity of the virus and its potential causal role in the observed cases of microcephaly and other neurological disorders.

abstract:
  On 1 February 2016, the World Health Organization (WHO) declared that clusters of microcephaly cases and other neurological disorders occurring in Zika virus (ZIKV)-affected areas constituted a public health emergency of international concern. Increased surveillance of the virus, including the requirement for laboratory confirmation of infection, was recommended. The WHO Regional Office for the Western Pacific therefore initiated a rapid survey among national-level public health laboratories in 19 countries and areas to determine regional capacity for ZIKV detection. The survey indicated that 16/19 (84%) countries had capacity for molecular detection of ZIKV while others facilitated testing through referral. These results suggest that robust laboratory capacity is in place to support ZIKV surveillance in the Western Pacific Region.


id: cord-002341-v4r5d26a
author: Chan, Jasper Fuk-Woo
date: 2016-11-12
txt: ./txt/cord-002341-v4r5d26a.txt
cache: ./cache/cord-002341-v4r5d26a.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161441/
doi: 10.1016/j.ebiom.2016.11.017
summary:
  To establish a novel mouse model for ZIKV infection, we compared the clinical, histological, and virological findings of male (group 1) and female (group 2) mice with dexamethasone immunosuppression and ZIKV inoculation with those of the appropriate controls (groups 3 to 8) (Table 1 ). The dexamethasone-immunosuppressed mice with ZIKV inoculation in our study developed disseminated infection with viremia and multi-organ involvement, including the brain, urogenital tract, intestine, liver, spleen, pancreas, heart, lung, and salivary gland as evident by ZIKV-NS1 protein expression on immunohistochemical staining and/or detectable viral load in these tissues. Our findings provided an additional explanation for the pathogenesis of fatal ZIKV infection, which has been proposed to be related to uncontrolled virus dissemination in previously described mouse models utilizing types I/II interferon-signaling-/receptor-deficient mice that were unable to mount a robust host innate immune response.

title:
  Zika Virus Infection in Dexamethasone-immunosuppressed Mice Demonstrating Disseminated Infection with Multi-organ Involvement Including Orchitis Effectively Treated by Recombinant Type I Interferons

abstract:
  BACKGROUND: Disseminated or fatal Zika virus (ZIKV) infections were reported in immunosuppressed patients. Existing interferon-signaling/receptor-deficient mouse models may not be suitable for evaluating treatment effects of recombinant interferons. METHODS: We developed a novel mouse model for ZIKV infection by immunosuppressing BALB/c mice with dexamethasone. RESULTS: Dexamethasone-immunosuppressed male mice (6–8 weeks) developed disseminated infection as evidenced by the detection of ZIKV-NS1 protein expression and high viral loads in multiple organs. They had ≥ 10% weight loss and high clinical scores soon after dexamethasone withdrawal (10 dpi), which warranted euthanasia at 12 dpi. Viral loads in blood and most tissues at 5 dpi were significantly higher than those at 12 dpi (P < 0.05). Histological examination revealed prominent inflammatory infiltrates in multiple organs, and CD45 + and CD8 + inflammatory cells were seen in the testis. These findings suggested that clinical deterioration occurred during viral clearance by host immune response. Type I interferon treatments improved clinical outcome of mice (100% vs 0% survival). CONCLUSIONS: Besides virus dissemination, inflammation of various tissues, especially orchitis, may be potential complications of ZIKV infection with significant implications on disease transmission and male fertility. Interferon treatment should be considered in patients at high risks for ZIKV-associated complications when the potential benefits outweigh the side effects of treatment.


id: cord-002581-r7mskri0
title: A human inferred germline antibody binds to an immunodominant epitope and neutralizes Zika virus
author: Magnani, Diogo M.
date: 2017-06-12
txt: ./txt/cord-002581-r7mskri0.txt
cache: ./cache/cord-002581-r7mskri0.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481143/
doi: 10.1371/journal.pntd.0005655
summary:
  title: A human inferred germline antibody binds to an immunodominant epitope and neutralizes Zika virus The isolation of neutralizing monoclonal antibodies (nmAbs) against the Zika virus (ZIKV) might lead to novel preventative strategies for infections in at-risk individuals, primarily pregnant women. Here we describe the isolation of 18 plasmablast-derived human mAbs, sorted 12 days post onset of symptoms from a ZIKV-patient in São Paulo, Brazil. Interestingly, one of these mAbs (P1F12) exhibited no nucleotide mutations when compared to its corresponding germline sequences, but still recognized a ZIKV immunodominant epitope and neutralized the virus. Virus capture assay and recombinant E protein ELISA P1F12 binding was determined by both virus capture assay (VCA) and recombinant (r)E ELISAs. The VCA plates were coated overnight with the mouse-anti-Flavivirus monoclonal antibody 4G2 (clone D1-4G2-4-15, EMD Millipore) followed by incubation with viral stocks (ZIKV or DENV). Molecular determinants of human neutralizing antibodies isolated from a patient infected with Zika virus

abstract:
  The isolation of neutralizing monoclonal antibodies (nmAbs) against the Zika virus (ZIKV) might lead to novel preventative strategies for infections in at-risk individuals, primarily pregnant women. Here we describe the characterization of human mAbs from the plasmablasts of an acutely infected patient. One of the 18 mAbs had the unusual feature of binding to and neutralizing ZIKV despite not appearing to have been diversified by affinity maturation. This mAb neutralized ZIKV (Neut(50) ~ 2 μg/ml) but did not react with any of the four dengue virus serotypes. Except for the expected junctional diversity created by the joining of the V-(D)-J genes, there was no deviation from immunoglobulin germline genes. This is a rare example of a human mAb with neutralizing activity in the absence of detectable somatic hypermutation. Importantly, binding of this mAb to ZIKV was specifically inhibited by human plasma from ZIKV-exposed individuals, suggesting that it may be of value in a diagnostic setting.


id: cord-002720-lrkscs71
author: Kurosaki, Yohei
date: 2017-10-18
txt: ./txt/cord-002720-lrkscs71.txt
cache: ./cache/cord-002720-lrkscs71.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647432/
doi: 10.1038/s41598-017-13836-9
summary:
  title: Development and evaluation of a rapid molecular diagnostic test for Zika virus infection by reverse transcription loop-mediated isothermal amplification The assay detected viral RNA at 14.5 TCID(50)/mL in virus-spiked serum or urine samples within 15 min, although it was slightly less sensitive than reference real time RT-PCR assay. We then evaluated the utility of this assay as a molecular diagnostic test using 90 plasma or serum samples and 99 urine samples collected from 120 suspected cases of arbovirus infection in the states of Paraíba and Pernambuco, Brazil in 2016. Therefore, it is difficult to detect ZIKV in blood samples from patients after the acute phase of infection, even with sensitive molecular diagnostic methods, such as reverse transcription-polymerase chain reaction (RT-PCR) 14, 18, 19 . These results suggested that the RT-LAMP assay could be used as a rapid, sensitive diagnostic test for ZIKV, the Tp value (i.e., less than 15 min) can be used as an indicator of the number of RNA copies in each reaction.

title:
  Development and evaluation of a rapid molecular diagnostic test for Zika virus infection by reverse transcription loop-mediated isothermal amplification

abstract:
  The recent outbreak of Zika virus (ZIKV) disease caused an enormous number of infections in Central and South America, and the unusual increase in the number of infants born with microcephaly associated with ZIKV infection aroused global concern. Here, we developed a reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay using a portable device for the detection of ZIKV. The assay specifically detected ZIKV strains of both Asian and African genotypes without cross-reactivity with other arboviruses, including Dengue and Chikungunya viruses. The assay detected viral RNA at 14.5 TCID(50)/mL in virus-spiked serum or urine samples within 15 min, although it was slightly less sensitive than reference real time RT-PCR assay. We then evaluated the utility of this assay as a molecular diagnostic test using 90 plasma or serum samples and 99 urine samples collected from 120 suspected cases of arbovirus infection in the states of Paraíba and Pernambuco, Brazil in 2016. The results of this assay were consistent with those of the reference RT-PCR test. This portable RT-LAMP assay was highly specific for ZIKV, and enable rapid diagnosis of the virus infection. Our results provide new insights into ZIKV molecular diagnostics and may improve preparedness for future outbreaks.


id: cord-002754-xlk4xpv2
author: Mögling, Ramona
date: 2017-09-07
txt: ./txt/cord-002754-xlk4xpv2.txt
cache: ./cache/cord-002754-xlk4xpv2.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685210/
doi: 10.2807/1560-7917.es.2017.22.36.30609
summary:
  title: Status, quality and specific needs of Zika virus (ZIKV) diagnostic capacity and capability in National Reference Laboratories for arboviruses in 30 EU/EEA countries, May 2016 To assess the capacity, quality, operational specifics (guidelines and algorithms), technical and interpretation issues and other possible difficulties that were related to ZIKV diagnostics in European countries, a questionnaire was conducted among national reference laboratories in 30 countries in the European Union/European Economic Area (EU/EEA) in May 2016. To map ZIKV expertise and identify diagnostic capacity and capability gaps in Europe during the initial phase of the PHEIC in February 2016, the European Commission (EC) asked the European Centre for Disease Prevention and Control (ECDC) for a rapid assessment of the capacity of laboratories in Europe to detect ZIKV infections and the specific needs for support. The availability of validation materials, positive controls and personnel were indicated as the main challenges for implementation of ZIKV diagnostics in the reference laboratories of the 30 EU/EEA countries.

title:
  Status, quality and specific needs of Zika virus (ZIKV) diagnostic capacity and capability in National Reference Laboratories for arboviruses in 30 EU/EEA countries, May 2016

abstract:
  With international travel, Zika virus (ZIKV) is introduced to Europe regularly. A country's ability to robustly detect ZIKV introduction and local transmission is important to minimise the risk for a ZIKV outbreak. Therefore, sufficient expertise and diagnostic capacity and capability are required in European laboratories. To assess the capacity, quality, operational specifics (guidelines and algorithms), technical and interpretation issues and other possible difficulties that were related to ZIKV diagnostics in European countries, a questionnaire was conducted among national reference laboratories in 30 countries in the European Union/European Economic Area (EU/EEA) in May 2016. While the coverage and capacity of ZIKV diagnostics in the EU/EEA national reference laboratories were found to be adequate, the assessment of the quality and needs indicated several crucial points of improvement that will need support at national and EU/EEA level to improve ZIKV preparedness, response and EU/EEA ZIKV surveillance activities.


id: cord-003041-v9uevz3l
author: Zukor, Katherine
date: 2018-02-23
txt: ./txt/cord-003041-v9uevz3l.txt
cache: ./cache/cord-003041-v9uevz3l.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992253/
doi: 10.1007/s13365-017-0595-z
summary:
  This study demonstrates that a contemporary strain of ZIKV can widely infect astrocytes and neurons in the brain and spinal cord of adult, interferon α/β receptor knockout mice (AG129 strain) and cause progressive hindlimb paralysis, as well as severe seizure-like activity during the acute phase of disease. This study demonstrates that a contemporary strain of ZIKV can widely infect astrocytes and neurons in the brain and spinal cord of adult, interferon α/β receptor knockout mice (AG129 strain) and cause progressive hindlimb paralysis, as well as severe seizurelike activity during the acute phase of disease. This study demonstrates that a contemporary strain of ZIKV (PRVABC59) can widely infect astrocytes and neurons in the brain and spinal cord of adult AG129 mice and cause rapidly progressing hindlimb paralysis, as well as severe seizure activity, during the acute phase of disease.

title:
  Zika virus-induced acute myelitis and motor deficits in adult interferon αβ/γ receptor knockout mice

abstract:
  Zika virus (ZIKV) has received widespread attention because of its effect on the developing fetus. It is becoming apparent, however, that severe neurological sequelae, such as Guillian-Barrë syndrome (GBS), myelitis, encephalitis, and seizures can occur after infection of adults. This study demonstrates that a contemporary strain of ZIKV can widely infect astrocytes and neurons in the brain and spinal cord of adult, interferon α/β receptor knockout mice (AG129 strain) and cause progressive hindlimb paralysis, as well as severe seizure-like activity during the acute phase of disease. The severity of hindlimb motor deficits correlated with increased numbers of ZIKV-infected lumbosacral spinal motor neurons and decreased numbers of spinal motor neurons. Electrophysiological compound muscle action potential (CMAP) amplitudes in response to stimulation of the lumbosacral spinal cord were reduced when obvious motor deficits were present. ZIKV immunoreactivity was high, intense, and obvious in tissue sections of the brain and spinal cord. Infection in the brain and spinal cord was also associated with astrogliosis as well as T cell and neutrophil infiltration. CMAP and histological analysis indicated that peripheral nerve and muscle functions were intact. Consequently, motor deficits in these circumstances appear to be primarily due to myelitis and possibly encephalitis as opposed to a peripheral neuropathy or a GBS-like syndrome. Thus, acute ZIKV infection of adult AG129 mice may be a useful model for ZIKV-induced myelitis, encephalitis, and seizure activity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13365-017-0595-z) contains supplementary material, which is available to authorized users.


id: cord-003187-qdbcdn2j
author: Bassi, Maria Rosaria
date: 2018-08-27
txt: ./txt/cord-003187-qdbcdn2j.txt
cache: ./cache/cord-003187-qdbcdn2j.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125542/
doi: 10.1128/aac.00380-18
summary:
  Although the two viruses are inhibited by the same three drugs, ZIKV is relatively more susceptive to serial passage in the presence of purine analogues (favipiravir and ribavirin), while USUV replication is suppressed more efficiently by 5-fluorouracil. We observe that ribavirin, favipiravir, and 5-fluorouracil are all inhibitors of both ZIKV and USUV, and that consecutive passage of virus in the presence of these drugs can lead to the complete extinction of infectivity. To investigate whether ZIKV replication could be affected by increased mutagenesis, we tested four different compounds known to be mutagenic for diverse viruses, 5-fluorouracil, ribavirin, favipiravir, and decitabine (25, 32, 35, (37) (38) (39) . To investigate whether the antiviral activities observed during treatment with favipiravir, ribavirin, and 5-fluorouracil are connected to their predicted mutagenic activity, we analyzed the mutation frequencies of both ZIKV and USUV rescued after 5 passages in the presence of these compounds.

title:
  Extinction of Zika Virus and Usutu Virus by Lethal Mutagenesis Reveals Different Patterns of Sensitivity to Three Mutagenic Drugs

abstract:
  Flaviviruses constitute an increasing source of public health concern, with growing numbers of pathogens causing disease and geographic spread to temperate climates. Despite a large body of evidence supporting mutagenesis as a conceivable antiviral strategy, there are currently no data on the sensitivity to increased mutagenesis for Zika virus (ZIKV) and Usutu virus (USUV), two emerging flaviviral threats. In this study, we demonstrate that both viruses are sensitive to three ribonucleosides, favipiravir, ribavirin, and 5-fluorouracil, that have shown mutagenic activity against other RNA viruses while remaining unaffected by a mutagenic deoxyribonucleoside. Serial cell culture passages of ZIKV in the presence of these compounds resulted in the rapid extinction of infectivity, suggesting elevated sensitivity to mutagenesis. USUV extinction was achieved when a 10-fold dilution was applied between every passage, but not in experiments involving undiluted virus, indicating an overall lower susceptibility than ZIKV. Although the two viruses are inhibited by the same three drugs, ZIKV is relatively more susceptive to serial passage in the presence of purine analogues (favipiravir and ribavirin), while USUV replication is suppressed more efficiently by 5-fluorouracil. These differences in sensitivity typically correlate with the increases in the mutation frequencies observed in each nucleoside treatment. These results are relevant to the development of efficient therapies based on lethal mutagenesis and support the rational selection of different mutagenic nucleosides for each pathogen. We will discuss the implications of these results to the fidelity of flavivirus replication and the design of antiviral therapies based on lethal mutagenesis.


id: cord-003284-hjx2d5rq
author: Márquez-Jurado, Silvia
date: 2018-10-07
txt: ./txt/cord-003284-hjx2d5rq.txt
cache: ./cache/cord-003284-hjx2d5rq.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212934/
doi: 10.3390/v10100547
summary:
  Furthermore, using this infectious clone we have generated a mutant ZIKV containing a single amino acid substitution (A175V) in the NS2A protein that presented reduced viral RNA synthesis in cell cultures, was highly attenuated in vivo and induced fully protection against a lethal challenge with ZIKV wild-type. To analyze the genetic stability of the recombinant ZIKV harboring the point mutation A175V in the coding region of the NS2A protein (rZIKV-RGN-mNS2A), total RNA was purified from Vero cells infected with viruses from passage 1 (P1) to passage 5 (P5) using the RNeasy minikit (Qiagen), according to the manufacturer''s specifications. To investigate whether the reduced RNA synthesis of rZIKV-RGN-mNS2A in Vero cells could result in viral attenuation in vivo, the ability of the mutant virus to induce pathogenesis was analyzed in A129 mice and compared with that of the parental rZIKV-RGN ( Figure 6 ).

title:
  An Alanine-to-Valine Substitution in the Residue 175 of Zika Virus NS2A Protein Affects Viral RNA Synthesis and Attenuates the Virus In Vivo

abstract:
  The recent outbreaks of Zika virus (ZIKV), its association with Guillain–Barré syndrome and fetal abnormalities, and the lack of approved vaccines and antivirals, highlight the importance of developing countermeasures to combat ZIKV disease. In this respect, infectious clones constitute excellent tools to accomplish these goals. However, flavivirus infectious clones are often difficult to work with due to the toxicity of some flavivirus sequences in bacteria. To bypass this problem, several alternative approaches have been applied for the generation of ZIKV clones including, among others, in vitro ligation, insertions of introns and using infectious subgenomic amplicons. Here, we report a simple and novel DNA-launched approach based on the use of a bacterial artificial chromosome (BAC) to generate a cDNA clone of Rio Grande do Norte Natal ZIKV strain. The sequence was identified from the brain tissue of an aborted fetus with microcephaly. The BAC clone was fully stable in bacteria and the infectious virus was efficiently recovered in Vero cells through direct delivery of the cDNA clone. The rescued virus yielded high titers in Vero cells and was pathogenic in a validated mouse model (A129 mice) of ZIKV infection. Furthermore, using this infectious clone we have generated a mutant ZIKV containing a single amino acid substitution (A175V) in the NS2A protein that presented reduced viral RNA synthesis in cell cultures, was highly attenuated in vivo and induced fully protection against a lethal challenge with ZIKV wild-type. This BAC approach provides a stable and reliable reverse genetic system for ZIKV that will help to identify viral determinants of virulence and facilitate the development of vaccine and therapeutic strategies.


id: cord-003403-ypefqm71
title: Assay Challenges for Emerging Infectious Diseases: The Zika Experience
author: Roberts, Christine C.
date: 2018-10-02
txt: ./txt/cord-003403-ypefqm71.txt
cache: ./cache/cord-003403-ypefqm71.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313918/
doi: 10.3390/vaccines6040070
summary:
  When initial Zika vaccine clinical trials were being designed and launched in response to the outbreak, there were no standardized sets of viral and immunological assays, and no approved diagnostic tests for Zika virus infection. In an outbreak situation, such as with Zika, it is important to have the ability to quickly develop both diagnostic kits for public health purposes and vaccine clinical assays to support pre-clinical studies and early stage clinical trials. Additionally, cross-reactivity in a number of immunological assays and the short time frame in which viremia can be detected in bodily fluids necessitated the institution of an algorithm to confirm ZIKV infection that was based on a combination of risk factors, clinical symptoms and diagnostic test results [71] . Rapid response to an emerging infectious disease-lessons learned from development of a synthetic DNA vaccine targeting Zika virus

abstract:
  From the perspective of vaccine development, it is imperative to accurately diagnose target infections in order to exclude subjects with prior exposure from evaluations of vaccine effectiveness, to track incident infection during the course of a clinical trial and to differentiate immune reactions due to natural infections from responses that are vaccine related. When vaccine development is accelerated to a rapid pace in response to emerging infectious disease threats, the challenges to develop such diagnostic tools is even greater. This was observed through the recent expansion of Zika virus infections into the Western Hemisphere in 2014–2017. When initial Zika vaccine clinical trials were being designed and launched in response to the outbreak, there were no standardized sets of viral and immunological assays, and no approved diagnostic tests for Zika virus infection. The diagnosis of Zika virus infection is still an area of active research and development on many fronts. Here we review emerging infectious disease vaccine clinical assay development and trial execution with a special focus on the state of Zika virus clinical assays and diagnostics.


id: cord-003453-p2buyrcj
title: Natural Products Isolated from Oriental Medicinal Herbs Inactivate Zika Virus
author: Batista, Mariana N.
date: 2019-01-11
txt: ./txt/cord-003453-p2buyrcj.txt
cache: ./cache/cord-003453-p2buyrcj.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356660/
doi: 10.3390/v11010049
summary:
  In this study, we tested the activity of the natural compounds berberine and emodin for their ability to inhibit ZIKV infection. The supernatant containing infectious virus particles was incubated for 1 h at different concentrations of each compound (berberine: 20-160 µM and emodin: 0.04-40 µM) and subsequently used to infect Vero E6 cells. The supernatant containing infectious virus particles was incubated for 1 h at different concentrations of each compound (berberine: 20-160 µM and emodin: 0.04-40 µM) and subsequently used to infect Vero E6 cells. Vero E6 cells were incubated with berberine or emodin for 1 h at the highest non-toxic concentrations prior to ZIKV infection. Vero E6 cells were incubated with berberine or emodin for 1 h at the highest non-toxic concentrations prior to ZIKV infection. Vero E6 cells were incubated with berberine or emodin for 1 h at the highest non-toxic concentrations prior to ZIKV infection.

abstract:
  Zika virus (ZIKV) has been associated with serious health conditions, and an intense search to discover different ways to prevent and treat ZIKV infection is underway. Berberine and emodin possess several pharmacological properties and have been shown to be particularly effective against the entry and replication of several viruses. We show that emodin and berberine trigger a virucidal effect on ZIKV. When the virus was exposed to 160 µM of berberine, a reduction of 77.6% in the infectivity was observed; when emodin was used (40 µM), this reduction was approximately 83.3%. Dynamic light scattering data showed that both compounds significantly reduce the hydrodynamic radius of virus particle in solution. We report here that berberine and emodin, two natural compounds, have strong virucidal effect in Zika virus.


id: cord-003482-f1uvohf0
author: Malmlov, Ashley
date: 2019-02-04
txt: ./txt/cord-003482-f1uvohf0.txt
cache: ./cache/cord-003482-f1uvohf0.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382173/
doi: 10.1371/journal.pntd.0007071
summary:
  Quantitative probe-based reverse transcription PCR (qRT-PCR) was performed on seruminoculated Vero cell supernatants, serum, brain, lung, liver, spleen, kidney, urinary bladder, prostate and testes from bats from both studies. Brain and testicular tissues stained with both goat polyclonal goat anti-Iba1 (green) and monoclonal 4G-2 flavivirus E specific antibodies (red) showed co-localization (yellow) of ZIKV antigen in cytoplasm of activated microglial cells with their characteristic morphology in the cerebral cortex of infected bats 10 dpi in the time course study and 28 day dpi in the pilot study (Fig 9) . Two bat infection experiments were conducted in this investigation; 1) a pilot study to determine susceptibility of Jamaican fruit bats to ZIKV infection, and 2) a time course study to better understand pathophysiology and chronology of events pertaining to the dynamics of viremia, viral tropism, replication and shedding of the virus in a New World bat species.

title:
  Experimental Zika virus infection of Jamaican fruit bats (Artibeus jamaicensis) and possible entry of virus into brain via activated microglial cells

abstract:
  The emergence of Zika virus (ZIKV) in the New World has led to more than 200,000 human infections. Perinatal infection can cause severe neurological complications, including fetal and neonatal microcephaly, and in adults there is an association with Guillain-Barré syndrome (GBS). ZIKV is transmitted to humans by Aedes sp. mosquitoes, yet little is known about its enzootic cycle in which transmission is thought to occur between arboreal Aedes sp. mosquitos and non-human primates. In the 1950s and ‘60s, several bat species were shown to be naturally and experimentally susceptible to ZIKV with acute viremia and seroconversion, and some developed neurological disease with viral antigen detected in the brain. Because of ZIKV emergence in the Americas, we sought to determine susceptibility of Jamaican fruit bats (Artibeus jamaicensis), one of the most common bats in the New World. Bats were inoculated with ZIKV PRVABC59 but did not show signs of disease. Bats held to 28 days post-inoculation (PI) had detectable antibody by ELISA and viral RNA was detected by qRT-PCR in the brain, saliva and urine in some of the bats. Immunoreactivity using polyclonal anti-ZIKV antibody was detected in testes, brain, lung and salivary glands plus scrotal skin. Tropism for mononuclear cells, including macrophages/microglia and fibroblasts, was seen in the aforementioned organs in addition to testicular Leydig cells. The virus likely localized to the brain via infection of Iba1(+) macrophage/microglial cells. Jamaican fruit bats, therefore, may be a useful animal model for the study of ZIKV infection. This work also raises the possibility that bats may have a role in Zika virus ecology in endemic regions, and that ZIKV may pose a wildlife disease threat to bat populations.


id: cord-004020-qtwcbn7m
title: Identification of Novel Natural Products as Effective and Broad-Spectrum Anti-Zika Virus Inhibitors
author: Gao, Yaning
date: 2019-11-02
txt: ./txt/cord-004020-qtwcbn7m.txt
cache: ./cache/cord-004020-qtwcbn7m.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893700/
doi: 10.3390/v11111019
summary:
  A combination of gossypol with any of the three natural products identified in this study, as well as with bortezomib, a previously reported anti-ZIKV compound, exhibited significant combinatorial inhibitory effects against three ZIKV human strains tested. Gossypol-treated ZIKV was incubated with Vero E6 cells at 37 • C for 1 h in the presence of DMEM containing serial dilutions of each of the other three natural products identified, such as curcumin, digitonin, and conessine, or anti-ZIKV compound control (bortezomib). Based on Table 1 , four "hit" natural products, including gossypol, curcumin, digitonin, and conessine ( Figure 2A -D), were selected, since they demonstrated inhibitory activity against ZIKV infection with no obvious cytotoxicity in Vero E6 cells when observed under a microscope. Since gossypol demonstrated the highest antiviral activity individually against all ZIKV strains tested, we next investigated the potential combinatorial effects of the combination of gossypol with three other natural products identified, namely curcumin, digitonin, and conessine, as well as anti-ZIKV compound control (bortezomib).

abstract:
  Zika virus (ZIKV) infection during pregnancy leads to severe congenital Zika syndrome, which includes microcephaly and other neurological malformations. No therapeutic agents have, so far, been approved for the treatment of ZIKV infection in humans; as such, there is a need for a continuous effort to develop effective and safe antiviral drugs to treat ZIKV-caused diseases. After screening a natural product library, we have herein identified four natural products with anti-ZIKV activity in Vero E6 cells, including gossypol, curcumin, digitonin, and conessine. Except for curcumin, the other three natural products have not been reported before to have anti-ZIKV activity. Among them, gossypol exhibited the strongest inhibitory activity against almost all 10 ZIKV strains tested, including six recent epidemic human strains. The mechanistic study indicated that gossypol could neutralize ZIKV infection by targeting the envelope protein domain III (EDIII) of ZIKV. In contrast, the other natural products inhibited ZIKV infection by targeting the host cell or cell-associated entry and replication stages of ZIKV. A combination of gossypol with any of the three natural products identified in this study, as well as with bortezomib, a previously reported anti-ZIKV compound, exhibited significant combinatorial inhibitory effects against three ZIKV human strains tested. Importantly, gossypol also demonstrated marked potency against all four serotypes of dengue virus (DENV) human strains in vitro. Taken together, this study indicates the potential for further development of these natural products, particularly gossypol, as the lead compound or broad-spectrum inhibitors against ZIKV and other flaviviruses, such as DENV.


id: cord-004022-cr0zskcw
author: Lu, Chien-Yi
date: 2019-10-31
txt: ./txt/cord-004022-cr0zskcw.txt
cache: ./cache/cord-004022-cr0zskcw.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893733/
doi: 10.3390/v11111005
summary:
  The packaging cells carrying the recombinant plasmid encoding the viral structural proteins are transfected with DNA-launched replicons and then self-replicate viral subgenomes and express all viral proteins, allowing viral assembly and release as SRIPs. Several flavivirus, replicon-based SRIPs, including JEV, dengue virus, West Nile virus, and tick-borne encephalitis virus have been generated and demonstrated as safer vaccine candidates [15] [16] [17] . To examine the production of ZIKV Natal RGN SRIPs, the supernatant of replicon-transfected packaging cells was harvested 72 h post-transfection and analyzed using dot-blotting, real-time RT-PCR, and TCID50 assays (Figure 4) . To examine the production of ZIKV Natal RGN SRIPs, the supernatant of replicon-transfected packaging cells was harvested 72 h post-transfection and analyzed using dot-blotting, real-time RT-PCR, and TCID50 assays (Figure 4) .

title:
  The Rescue and Characterization of Recombinant, Microcephaly-Associated Zika Viruses as Single-Round Infectious Particles

abstract:
  Zika virus (ZIKV) is transmitted by Aedes mosquitoes and exhibits genetic variation with African and Asian lineages. ZIKV Natal RGN strain, an Asian-lineage virus, has been identified in brain tissues from fetal autopsy cases with microcephaly and is suggested to be a neurotropic variant. However, ZIKV Natal RGN strain has not been isolated; its biological features are not yet illustrated. This study rescued and characterized recombinant, single-round infectious particles (SRIPs) of the ZIKV Natal RGN strain using reverse genetic and synthetic biology techniques. The DNA-launched replicon of ZIKV Natal RGN was constructed and contains the EGFP reporter, lacks prM-E genes, and replicates under CMV promoter control. The peak in the ZIKV Natal RGN SRIP titer reached 6.25 × 10(6) TCID50/mL in the supernatant of prM-E-expressing packaging cells 72 h post-transfection with a ZIKV Natal RGN replicon. The infectivity of ZIKV Natal RGN SRIPs has been demonstrated to correlate with the green florescence intensity of the EGFP reporter, the SRIP-induced cytopathic effect, and ZIKV’s non-structural protein expression. Moreover, ZIKV Natal RGN SRIPs effectively self-replicated in rhabdomyosarcoma/muscle, glioblastoma/astrocytoma, and retinal pigmented epithelial cells, displaying unique cell susceptibility with differential attachment activity. Therefore, the recombinant ZIKV Natal RGN strain was rescued as SRIPs that could be used to elucidate the biological features of a neurotropic strain regarding cell tropism and pathogenic components, apply for antiviral agent screening, and develop vaccine candidates.


id: cord-004053-nmt221tu
title: Zika and Flavivirus Shell Disorder: Virulence and Fetal Morbidity
author: Goh, Gerard Kian-Meng
date: 2019-11-06
txt: ./txt/cord-004053-nmt221tu.txt
cache: ./cache/cord-004053-nmt221tu.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920988/
doi: 10.3390/biom9110710
summary:
  Percentages of intrinsic disorder (PIDs) of M and C shell proteins from Zika virus (ZIKV) strains with UniProt accession. According to our research on other viruses, the capsid association with virulence involves a mechanism of protein promiscuity, whereby intrinsic disorder allows the capsid protein (the C protein, in the case of flaviviruses) to bind to a greater number of proteins, thereby allowing the virus to multiply more rapidly before the host immune system can take action [2, 14, 51] . It is therefore likely that the different PIDs of C proteins from the various ZIKV strains and lineages are the result of the types of primates that the peculiar ZIKV strain primarily infects and its ability to fine-tune its C disorder to meet the optimal viral load necessary for more efficient transmission of the virus in a given host, as seen in the case of other viruses and other flaviviruses [2, 14, 25, 39, 49, 50] .

abstract:
  Zika virus (ZIKV) was first discovered in 1947 in Africa. Since then, sporadic ZIKV infections of humans have been reported in Africa and Asia. For a long time, this virus was mostly unnoticed due to its mild symptoms and low fatality rates. However, during the 2015–2016 epidemic in Central and South America, when millions of people were infected, it was discovered that ZIKV causes microcephaly in the babies of mothers infected during pregnancy. An examination of the M and C proteins of the ZIKV shell using the disorder predictor PONDR VLXT revealed that the M protein contains relatively high disorder levels comparable only to those of the yellow fever virus (YFV). On the other hand, the disorder levels in the C protein are relatively low, which can account for the low case fatality rate (CFR) of this virus in contrast to the more virulent YFV, which is characterized by high disorder in its C protein. A larger variation was found in the percentage of intrinsic disorder (PID) in the C protein of various ZIKV strains. Strains of African lineage are characterized by higher PIDs. Using both in vivo and in vitro experiments, laboratories have also previously shown that strains of African origin have a greater potential to inflict higher fetal morbidity than do strains of Asian lineage, with dengue-2 virus (DENV-2) having the least potential. Strong correlations were found between the potential to inflict fetal morbidity and shell disorder in ZIKV (r(2) = 0.9) and DENV-2 (DENV-2 + ZIKV, r(2) = 0.8). A strong correlation between CFR and PID was also observed when ZIKV was included in an analysis of sets of shell proteins from a variety of flaviviruses (r(2) = 0.8). These observations have potential implications for antiviral vaccine development and for the design of cancer therapeutics in terms of developing therapeutic viruses that penetrate hard-to-reach organs.


id: cord-004418-08dljap3
author: Young, Ginger
date: 2020-02-26
txt: ./txt/cord-004418-08dljap3.txt
cache: ./cache/cord-004418-08dljap3.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044319/
doi: 10.1038/s41598-020-60415-6
summary:
  In this study we evaluated the antibody responses and efficacy of an aluminum hydroxide adjuvanted purified inactivated Zika vaccine (PIZV) against challenge with Zika virus (ZIKV) strain PRVABC59. As with neutralizing antibodies, all PIZV doses were immunogenic and no anti-Zika IgG was detected in the control group prior to ZIKV challenge. PIZV elicited a dose dependent neutralizing antibody immune response and an anti-Zika IgG response which correlated with a reduction in ZIKV vRNA post-challenge (Table 2 ). Vaccinating with a broad range of PIZV dose levels enabled us to correlate both neutralizing and anti-Zika IgG antibody titers to protection against ZIKV infection. A Zika RVP assay (Sonnberg et al., manuscript in preparation) was used to determine neutralizing antibody titers in serum following the administration of PIZV (study days 1, 29, 57, and 71), and 30 days post-ZIKV challenge (day 101).

title:
  Complete Protection in Macaques Conferred by Purified Inactivated Zika Vaccine: Defining a Correlate of Protection

abstract:
  A critical global health need exists for a Zika vaccine capable of mitigating the effects of future Zika epidemics. In this study we evaluated the antibody responses and efficacy of an aluminum hydroxide adjuvanted purified inactivated Zika vaccine (PIZV) against challenge with Zika virus (ZIKV) strain PRVABC59. Indian rhesus macaques received two doses of PIZV at varying concentrations ranging from 0.016 µg − 10 µg and were subsequently challenged with ZIKV six weeks or one year following the second immunization. PIZV induced a dose-dependent immune response that was boosted by a second immunization. Complete protection against ZIKV infection was achieved with the higher PIZV doses of 0.4 µg, 2 µg, and 10 µg at 6 weeks and with 10 ug PIZV at 1 year following vaccination. Partial protection was achieved with the lower PIZV doses of 0.016 µg and 0.08 µg. Based on these data, a neutralizing antibody response above 3.02 log(10) EC50 was determined as a correlate of protection in macaques. PIZV elicited a dose-dependent neutralizing antibody response which is protective for at least 1 year following vaccination.


id: cord-009399-6zpkpdzu
title: Topology, Antiviral Functional Residues and Mechanism of IFITM1
author: Sun, Fang
date: 2020-03-08
txt: ./txt/cord-009399-6zpkpdzu.txt
cache: ./cache/cord-009399-6zpkpdzu.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150853/
doi: 10.3390/v12030295
summary:
  Further, KRRK basic residues of IFITM1 locating at 62–67 of the conserved intracellular loop (CIL) were found to play a key role in the restriction on the Zika virus (ZIKV) and dengue virus (DENV). Finally, IFITM1 was revealed to be capable of restricting the release of ZIKV particles from endosome to cytosol so as to impede the entry of ZIKV into host cells, which was tightly related with the inhibition of IFITM1 on the acidification of organelles. Some studies suggest that IFITM proteins may suppress the entry of viruses by inhibiting the hemifusion of viral membrane and host cell membranes [15] or restricting the formation of fusion pores following virus-endosome hemifusion [16] . Alanine scanning and site-directed mutations found that KRRK basic residues were key for the restriction of IFITM proteins on ZIKV and DENV. Significantly, we found that IFITM1 can restrict the release of ZIKV from endosome to cytosol to prevent the entry of viral particles into host cells, which was associated with its inhibition on organelles acidification.

abstract:
  Interferon-inducible transmembrane proteins (IFITM1/2/3) have been reported to suppress the entry of a wide range of viruses. However, their antiviral functional residues and specific mechanisms are still unclear. Here, we firstly resolved the topology of IFITM1 on the plasma membrane where N-terminus points into the cytoplasm and C-terminus resides extracellularly. Further, KRRK basic residues of IFITM1 locating at 62–67 of the conserved intracellular loop (CIL) were found to play a key role in the restriction on the Zika virus (ZIKV) and dengue virus (DENV). Similarly, KRRK basic residues of IFITM2/3 also contributed to suppressing ZIKV replication. Finally, IFITM1 was revealed to be capable of restricting the release of ZIKV particles from endosome to cytosol so as to impede the entry of ZIKV into host cells, which was tightly related with the inhibition of IFITM1 on the acidification of organelles. Overall, our study provided topology, antiviral functional residues and the mechanism of interferon-inducible transmembrane proteins.


id: cord-010119-t1x9gknd
title: Abstract Presentations from the AABB Annual Meeting San Diego, CA ctober 7‐10, 2017
author: nan
date: 2017-09-04
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url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169716/
doi: 10.1111/trf.14286
abstract: nan
summary:
  Conclusion: The wide distribution in the concentration of bioactive lipids among 405 stored RBC units suggests that lipid degradation is highly donor-Background/Case Studies: To ensure availability of biological products to hospitals, blood banks have developed and validated multiple storage conditions for each of their products to maximize shelf life and quality. 1 The Department of Blood Transfusion, The PLA General Hospital, 2 The Department of Blood Transfusion, Air Force General Hospital, PLA Background/Case Studies: Recently, multi researches have reported that longer term-stored red blood cells(RBCs) units were associated with increased risks of clinically adverse events, especially in critically ill patients. Weak D types 1, 2 and 3 express all the major RhD epitopes and these patients can be managed as RhD-positive, which may lead to a reduction in unnecessary Rh immunoglobulin (RhIG) administration and conservation of RhD-negative RBCs. Study Design/Method: RHD genotyping was performed on all patient samples with weaker than expected or discrepant RhD typing results, utilizing a commercially available genotyping kit manufactured by Immucor (RHD BeadChip).


id: cord-015352-2d02eq3y
title: ESPR 2017
author: nan
date: 2017-04-26
txt: ./txt/cord-015352-2d02eq3y.txt
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mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103096/
doi: 10.1007/s00247-017-3820-2
abstract: nan
summary:
  Lapierre; Montreal/CA Summary: Objectives: To review the classification of visceroatrial situs To describe the associated cardiac and non-cardiac anomalies To illustrate typical findings in fetuses, neonates and children To discuss the surgical consideration and the long-term follow-up in these patients Abstract: By definition, the type of situs is determined by the relationship between the atria and the adjacent organs. As is often the case, radiology in JIA is all about: knowing your clinicians (i.e. the pretest likelihood for disease) being technically eloquent (e.g. using high-resolution US probes, not delaying post-contrast MRI acquisitions) knowing what is normal (e.g. normal undulations in the articular surface, focal bone marrow signal variation) not being dogmatic about individual observations or measurements interpreting your findings in a clinical context The lecture will demonstrate similarities and differences among joints and modalities in children with variable-severity JIA.


id: cord-016796-g4kqqpy1
author: Bramhachari, Pallaval Veera
date: 2019-11-05
txt: ./txt/cord-016796-g4kqqpy1.txt
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mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7121190/
doi: 10.1007/978-981-15-1045-8_17
summary:
  As a part of modern research on immunotechniques, a diagnostic approach for chronic hepatitis C infection (CHC), detects specific antibody to HCV (anti-HCV) (indirect tests) and assays that can detect, quantify, or characterize components of HCV viral particles, viz. Nonetheless, recent studies on respiratory syncytial virus (RSV) developed Luciferase Immunoprecipitation Systems (LIPS) assay to detect IgG Antibodies against Human RSV G-Glycoprotein. Sensitive and specific detection of Crimean-Congo hemorrhagic fever virus (CCHFV) was developed employing specific IgM and IgG antibodies in human sera using recombinant CCHFV nucleoprotein as antigen in μ-capture and IgG immune complex (IC) ELISA tests (Emmerich et al. A rapid diagnostic platform for colorimetric differential detection of DENV and CHIKV viral infections was recently developed with a possibility to alter clinical diagnosis of acute febrile illnesses in resource-limited settings. This novel antibody demonstrates noteworthy specificity to identify H7N9 virus compared to homemade target-captured ELISA, qRT-PCR, and rapid influenza diagnostic test (RIDT) with high sensitivity (Chang et al.

title:
  Advanced Immunotechnological Methods for Detection and Diagnosis of Viral Infections: Current Applications and Future Challenges

abstract:
  Diagnosis and identification of viruses is an important component of diagnostic virology laboratory. Although various modes of diagnostic methods are now available at disposal, a vast majority of the diseases across the globe remain undiagnosed. This is largely due to the overlapping undifferentiated set of symptoms across myriad set of RNA and DNA viral diseases. As such, it becomes critical to take into consideration several factors for viral diagnosis ranging from the type and quality of specimen collected, time of specimen collection, mode of transport, accuracy, specificity, sensitivity, and the type of diagnostic method used. This chapter broadly emphasizes various methods on diagnostic virology ranging from the classical methods of diagnosis to the most recently developed molecular methods of detection of virus.


id: cord-102279-ena1usqv
author: Long, Rory K. M.
date: 2020-06-23
txt: ./txt/cord-102279-ena1usqv.txt
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mime: text/plain
url: https://doi.org/10.1101/2020.05.12.091611
doi: 10.1101/2020.05.12.091611
summary:
  projections of 3D STED image stacks show high intensity ERmoxGFP and Sec61β-GFP labeling in a 89 CER region and low intensity labeling in PER tubules in mock-infected cells ( Figure 1A ), as reported 90 previously by diffraction limited confocal microscopy (3). Density-based segmentation of the ERmoxGFP-96 and Sec61β-GFP-labelled ER of ZIKV-infected cells showed that the higher density crescent-shaped 97 CER region exhibited significant overlap with dsRNA-positive ER structures relative to the rest of 98 the ER ( Figure 1B ). Morphological comparison of the dsRNA-positive and -negative CER of 133 ZIKV-infected cells with the CER of mock-infected cells showed that the CER was composed of a 134 convoluted network of tubules for both the ERmoxGFP-and Sec61β-labeled ER ( Figure 3B ). 3D STED analysis showed a predominant distribution of both NS2B and 149 NS4B to the CER and more particularly to the dense ZIKV-induced crescent-shaped tubular matrix 150 in ERmoxGFP transfected U87 cells ( Figure 5A ).

title:
  Super Resolution Microscopy and Deep Learning Identify Zika Virus Reorganization of the Endoplasmic Reticulum

abstract:
  The endoplasmic reticulum (ER) is a complex subcellular organelle composed of diverse structures such as tubules, sheets and tubular matrices. Flaviviruses such as Zika virus (ZIKV) induce reorganization of endoplasmic reticulum (ER) membranes to facilitate viral replication. Here, using 3D super resolution microscopy, ZIKV infection is shown to induce the formation of dense tubular matrices associated with viral replication in the central ER. Viral non-structural proteins NS4B and NS2B associate with replication complexes within the ZIKV-induced tubular matrix and exhibit distinct ER distributions outside this central ER region. Deep neural networks trained to identify ZIKV-infected versus mock-infected cells successfully identified ZIKV-induced central ER tubular matrices as a determinant of viral infection. Super resolution microscopy and deep learning are therefore able to identify and localize morphological features of the ER and may be of use to screen for inhibitors of infection by ER-reorganizing viruses.


id: cord-102612-xx5l8r9e
title: Zika virus alters centrosome organization to suppress the innate immune response
author: Kodani, Andrew
date: 2020-09-15
txt: ./txt/cord-102612-xx5l8r9e.txt
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extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.09.15.298083
doi: 10.1101/2020.09.15.298083
summary:
  ZIKV infection or loss of CEP63 decreased the centrosomal localization and stability of TANK-binding kinase 1 (TBK1), a regulator of the innate immune response. ZIKV infection or loss of CEP63 also increased the centrosomal accumulation of the CEP63 interactors, Mindbomb1 (MIB1) and DTX4, ubiquitin ligases that respectively activate and degrade TBK1. In addition to identifying a mechanism by which CEP63 controls the innate immune responses in ZIKV infection, we propose that the altered centrosomal organization caused by altered CEP63 function may contribute to ZIKV-associated microcephaly. ZIKV infection in U87 cells did not affect either the localization or levels of the MCPH-associated proteins PLK4, STIL, SAS6, CDK5RAP2, CEP152, or WDR62 (Supplemental Figure 2A-D) . In summary, we have found that ZIKV NS3 localizes to the centrosome, recruits CEP63 and its binding partners MIB1 and DTX4 to ubiquitylate and degrade TBK1, a key regulator of the innate immune response.

abstract:
  Zika virus (ZIKV) is a flavivirus transmitted via mosquitoes and sex to cause congenital neurodevelopmental defects, including microcephaly. Inherited forms of microcephaly (MCPH) are associated with disrupted centrosome organization. Similarly, we found that ZIKV infection disrupted centrosome organization. ZIKV infection disrupted the organization of centrosomal proteins including CEP63, a MCPH-associated protein. The ZIKV nonstructural protein NS3 bound CEP63, and expression of NS3 was sufficient to alter centrosome architecture and CEP63 localization. Loss of CEP63 suppressed ZIKV-induced centrosome disorganization, indicating that ZIKV requires CEP63 to disrupt centrosome organization. ZIKV infection or loss of CEP63 decreased the centrosomal localization and stability of TANK-binding kinase 1 (TBK1), a regulator of the innate immune response. ZIKV infection or loss of CEP63 also increased the centrosomal accumulation of the CEP63 interactors, Mindbomb1 (MIB1) and DTX4, ubiquitin ligases that respectively activate and degrade TBK1. Therefore, we propose that ZIKV NS3 binds CEP63 to increase centrosomal DTX4 localization and destabilization of TBK1, thereby tempering the innate immune response. In addition to identifying a mechanism by which CEP63 controls the innate immune responses in ZIKV infection, we propose that the altered centrosomal organization caused by altered CEP63 function may contribute to ZIKV-associated microcephaly.


id: cord-102796-rr8qet8c
title: Emergence of evidence during disease outbreaks: lessons learnt from the Zika virus outbreak
author: Counotte, Michel J
date: 2020-03-18
txt: ./txt/cord-102796-rr8qet8c.txt
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mime: text/plain
url: https://doi.org/10.1101/2020.03.16.20036806
doi: 10.1101/2020.03.16.20036806
summary:
  We are continuously facing new disease outbreaks, including the new coronavirus (SARS-nCoV-2) in December 2019.The objective of this study was to describe the accumulation of evidence during the 2013-2016 Zika virus (ZIKV) outbreak in the Pacific and the Americas related to aetiological causal questions about congenital abnormalities and Guillain-Barre syndrome. In the 2013-2016 ZIKV outbreak, case reports, case series and basic research studies were published first. A strength of this study is the pre-specified hypothesis about the time to publication of aetiological 139 research and the use of data from systematic reviews that had screened and selected studies that 140 addressed the causal relationship between ZIKV infection and its adverse outcomes. The accumulation of evidence over time in new causal problems seems to follow a hierarchy where 225 case reports and case series were rapidly followed by basic research. Syndrome outbreak associated with Zika virus infection in French Polynesia: A case-control study

abstract:
  Introduction: Outbreaks of infectious diseases trigger an increase in scientific research and output. Early in outbreaks, evidence is scarce, but it accumulates rapidly. We are continuously facing new disease outbreaks, including the new coronavirus (SARS-nCoV-2) in December 2019.The objective of this study was to describe the accumulation of evidence during the 2013-2016 Zika virus (ZIKV) outbreak in the Pacific and the Americas related to aetiological causal questions about congenital abnormalities and Guillain-Barre syndrome. Methods: We hypothesised that the temporal sequence would follow a pre-specified order, according to study design. We assessed 1) how long it takes before findings from a specific study design appear, 2) how publication of preprints could reduce the time to publication and 3) how time to publication evolves over time. Results: We included 346 publications published between March 6, 2014 and January 1, 2019. In the 2013-2016 ZIKV outbreak, case reports, case series and basic research studies were published first. Case-control and cohort studies appeared between 400-700 days after ZIKV was first detected in the region of the study origin. Delay due to the publication process were lowest at the beginning of the outbreak. Only 4.6% of the publications was available as preprints. Discussion: The accumulation of evidence over time in new causal problems generally followed a hierarchy. Preprints reduced the delay to initial publication. Our methods can be applied to new emerging infectious diseases.


id: cord-253616-7jyui5ca
title: Harringtonine Inhibits Zika Virus Infection through Multiple Mechanisms
author: Lai, Zheng-Zong
date: 2020-09-07
txt: ./txt/cord-253616-7jyui5ca.txt
cache: ./cache/cord-253616-7jyui5ca.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32906689/
doi: 10.3390/molecules25184082
summary:
  To investigate the anti-ZIKV activity of harringtonine, we assessed the inhibition of virus infection in Vero cells with MOI = 0.01 under different concentrations of harringtonine for 48 h. Intracellular viral RNA levels, protein expression levels and virus progeny in supernatants were respectively determined by RT-qPCR, western blotting and fluorescent focus assay (FFA). The dose-dependent anti-ZIKV activities of harringtonine were observed to decrease viral RNA/protein production and progeny yield ( Figure 1B-D) , indicating that virus propagation was suppressed. Harringtonine (625 nM) was administered at different stages of ZIKV infection with MOI = 0.1, and then the levels of ZIKV RNA in cells, as well as virus titers in supernatants, were determined after 24 h treatment. Harringtonine (625 nM) was administered at different stages of ZIKV infection with MOI = 0.1, and then the levels of ZIKV RNA in cells, as well as virus titers in supernatants, were determined after 24 h treatment.

abstract:
  Mosquito-borne Zika virus (ZIKV) is a Flavivirus that came under intense study from 2014 to 2016 for its well-known ability to cause congenital microcephaly in fetuses and neurological Guillain–Barré disease in adults. Substantial research on screening antiviral agents against ZIKV and preventing ZIKV infection are globally underway, but Food and Drug Administration (FDA)-approved treatments are not available yet. Compounds from Chinese medicinal herbs may offer an opportunity for potential therapies for anti-ZIKV infection. In this study, we evaluated the antiviral efficacy of harringtonine against ZIKV. Harringtonine possessed anti-ZIKV properties against the binding, entry, replication, and release stage through the virus life cycle. In addition, harringtonine have strong virucidal effects in ZIKV and exhibited prophylaxis antiviral ability prior ZIKV infection. The antiviral activity also observed in the treatment against Japanese encephalitis reporter virus (RP9-GFP strain). Overall, this study demonstrated that harringtonine would be a favorable potential candidate for the development of anti-ZIKV infection therapies.


id: cord-257539-01s21vh0
title: Chloroquine, an Endocytosis Blocking Agent, Inhibits Zika Virus Infection in Different Cell Models
author: Delvecchio, Rodrigo
date: 2016-11-29
txt: ./txt/cord-257539-01s21vh0.txt
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mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/27916837/
doi: 10.3390/v8120322
summary:
  Immunofluorescence staining corroborated these results ( Figure 1B ) and additionally, chloroquine decreased the production of infectious ( Figure 1C ) and total ( Figure 1D ) virus particles, including defective viral particles, by ZIKV-infected cells. Incubation of Vero cells with chloroquine at 0 h postinfection had a greater impact on the production of ZIKV particles, decreasing viral RNA 64-fold over the controls ( Figure 3A ). To evaluate which step of the viral cycle was susceptible to inhibition, chloroquine was added to Vero cells at different time points post-infection with ZIKV MR766. To evaluate which step of the viral cycle was susceptible to inhibition, chloroquine was added to Vero cells at different time points post-infection with ZIKV MR766. Incubation of Vero cells with chloroquine at 0 h post-infection had a greater impact on the production of ZIKV particles, decreasing viral RNA 64-fold over the controls ( Figure 3A ).

abstract:
  Zika virus (ZIKV) infection in utero might lead to microcephaly and other congenital defects. Since no specific therapy is available thus far, there is an urgent need for the discovery of agents capable of inhibiting its viral replication and deleterious effects. Chloroquine is widely used as an antimalarial drug, anti-inflammatory agent, and it also shows antiviral activity against several viruses. Here we show that chloroquine exhibits antiviral activity against ZIKV in Vero cells, human brain microvascular endothelial cells, human neural stem cells, and mouse neurospheres. We demonstrate that chloroquine reduces the number of ZIKV-infected cells in vitro, and inhibits virus production and cell death promoted by ZIKV infection without cytotoxic effects. In addition, chloroquine treatment partially reveres morphological changes induced by ZIKV infection in mouse neurospheres.


id: cord-260336-kwzo8puo
author: Si, Lulu
date: 2019-09-27
txt: ./txt/cord-260336-kwzo8puo.txt
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extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fmicb.2019.02250
doi: 10.3389/fmicb.2019.02250
summary:
  Here we showed that intraperitoneally administered Z2 could also be distributed to testis and epididymis, resulting in the reduction of ZIKV RNA copies in testicular tissue and protection of testis and epididymis against ZIKV-induced pathological damage and poor sperm quality in type I interferon receptor-deficient A129 mice. Student''s unpaired two-tailed t-test was used to monitor the distribution of Z2 in male A129 mouse body and testicular tissue and to analyze the difference of viral RNA level in sera or tissues between Z2-and vehicle-treated A129 mice. ZIKV RNA copies in (A) testes, (B) epididymides, and (C) sperm of Z2-or vehicle-treated ZIKV-infected male A129 mice at day 16 were detected by qRT-PCR. Zika virus infection in the testicular tissue not only damages male testicular tissue, resulting in pathological lesion of testes and epididymides, but also produces ZIKV-infected semen, causing infertility.

title:
  A Peptide-Based Virus Inactivator Protects Male Mice Against Zika Virus-Induced Damage of Testicular Tissue

abstract:
  Zika virus (ZIKV) was a re-emerging arbovirus associated with Guillain–Barré Syndrome in adult and congenital Zika syndrome in fetus and infant. Although ZIKV was mainly transmitted by mosquito bites, many sexual transmission cases have been reported since the outbreak in 2015. ZIKV can persist in testis and semen for a long time, causing testicular tissue damage and reducing sperm quality. However, no drug has been approved for prevention or treatment of ZIKV infection, especially infection in male testicular tissue. Previously reported peptide Z2 could inactivate ZIKV, inhibiting ZIKV infection in vitro and in vivo. Importantly, Z2 could inhibit vertical transmission of ZIKV in pregnant mice, reducing ZIKV infection in fetus. Here we showed that intraperitoneally administered Z2 could also be distributed to testis and epididymis, resulting in the reduction of ZIKV RNA copies in testicular tissue and protection of testis and epididymis against ZIKV-induced pathological damage and poor sperm quality in type I interferon receptor-deficient A129 mice. Thus, Z2, a ZIKV inactivator, could serve as an antiviral agent for treatment of ZIKV infection and attenuation of ZIKV-induced testicular tissue damage.


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

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


id: cord-263868-ewnf96cz
title: Chemical proteomics tracks virus entry and uncovers NCAM1 as Zika virus receptor
author: Srivastava, Mayank
date: 2020-08-04
txt: ./txt/cord-263868-ewnf96cz.txt
cache: ./cache/cord-263868-ewnf96cz.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41467-020-17638-y
doi: 10.1038/s41467-020-17638-y
summary:
  ZIKV was labeled on its surface with a chemical probe, which carries a photocrosslinker to covalently link virus-interacting proteins in living cells on UV exposure at different time points, and a biotin tag for subsequent enrichment and mass spectrometric identification of the receptor or other host proteins critical for virus internalization. We used the labeled ZIKV to infect Vero cells and interacting proteins were crosslinked at fixed time points to identify the virus-host factors and elucidate the virus entry mechanism (Fig. 1c) . To further investigate whether the strategy was also capable of correlating spatial information with the virus crosslinked proteins, we performed the STRING analysis to determine whether there is statistical overrepresentation of specific genes or proteins in the sample at specific time points and identify proteins specific at the attachment or cellular entry stages ( Supplementary Fig. 6 ).

abstract:
  The outbreak of Zika virus (ZIKV) in 2016 created worldwide health emergency which demand urgent research efforts on understanding the virus biology and developing therapeutic strategies. Here, we present a time-resolved chemical proteomic strategy to track the early-stage entry of ZIKV into host cells. ZIKV was labeled on its surface with a chemical probe, which carries a photocrosslinker to covalently link virus-interacting proteins in living cells on UV exposure at different time points, and a biotin tag for subsequent enrichment and mass spectrometric identification of the receptor or other host proteins critical for virus internalization. We identified Neural Cell Adhesion Molecule (NCAM1) as a potential ZIKV receptor and further validated it through overexpression, knockout, and inhibition of NCAM1 in Vero cells and human glioblastoma cells U-251 MG. Collectively, the strategy can serve as a universal tool to map virus entry pathways and uncover key interacting proteins.


id: cord-272405-jmwn8pdn
title: Evolution and Emergence of Pathogenic Viruses: Past, Present, and Future
author: Parvez, Mohammad K.
date: 2017-08-04
txt: ./txt/cord-272405-jmwn8pdn.txt
cache: ./cache/cord-272405-jmwn8pdn.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1159/000478729
doi: 10.1159/000478729
summary:
  Despite substantial advancements in the understanding of the biology of pathogens, the breakthroughs in prevention, and their effects on public health and the global economy, the emergence of novel pandemic viruses remains an enduring puzzle. This review presents an update on the knowledge of important emerging/re-emerging viral infections worldwide, discussing their possible origin, evolution, natural reservoirs, human adaptations, and risk factors ( Fig. 1 ). To understand this further, a recently isolated HEV genotype 3 from a chronic hepatitis E patient containing a recombinant virus-host RNA genome was shown to infect cultured human, pig, and deer hepatocytes [39] . The field of phylodynamics, combining a modeling framework for host, epidemiological, and molecular data, especially for RNA viruses, shows particular promise for Parvez understanding the patterns of viral evolution during epidemics [40, 41] . Despite landmark advances in understanding the nature and biology of many pathogenic viruses, there is limited knowledge on emerging novel viruses, their potential reservoirs, and their modes of transmission.

abstract:
  Incidences of emerging/re-emerging deadly viral infections have significantly affected human health despite extraordinary progress in the area of biomedical knowledge. The best examples are the recurring outbreaks of dengue and chikungunya fever in tropical and sub-tropical regions, the recent epidemic of Zika in the Americas and the Caribbean, and the SARS, MERS, and influenza A outbreaks across the globe. The established natural reservoirs of human viruses are mainly farm animals, and, to a lesser extent, wild animals and arthropods. The intricate “host-pathogen-environment” relationship remains the key to understanding the emergence/re-emergence of pathogenic viruses. High population density, rampant constructions, poor sanitation, changing climate, and the introduction of anthropophilic vectors create selective pressure on host-pathogen reservoirs. Nevertheless, the knowledge and understanding of such zoonoses and pathogen diversity in their known non-human reservoirs are very limited. Prevention of arboviral infections using vector control methods has not been very successful. Currently, new approaches to protect against food-borne infections, such as consuming only properly cooked meats and animal products, are the most effective control measures. Though significant progress in controlling human immunodeficiency virus and hepatitis viruses has been achieved, the unpredictable nature of evolving viruses and the rare occasions of outbreaks severely hamper control and preventive modalities.


id: cord-273065-peqz7okh
title: Arboviruses: A global public health threat
author: Girard, Marc
date: 2020-04-24
txt: ./txt/cord-273065-peqz7okh.txt
cache: ./cache/cord-273065-peqz7okh.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0264410X20304709
doi: 10.1016/j.vaccine.2020.04.011
summary:
  The repeated occurrence of recent deadly epidemics strongly reinforces the call for action against these viral diseases, and the need for developing effective vaccines, drugs, vector control tools and strong prevention programs. The recent outbreak of neurological disorders and neonatal malformations associated with Zika virus (ZIKV) infection in Latin America {5}, the yellow fever (YFV) epidemics in Angola and Brazil with importation to China [6] , the ever-expanding West Nile virus (WNV) epidemic in the Americas [7] , the recent emergence in East Africa and global spread of chikungunya virus (CHIKV) [8] , as well as the ongoing and expanding dengue virus (DENV) pandemic in the tropics and subtropics [9] have reinforced the call for action in the fight against emerging and re-emerging arboviral diseases. The vaccine showed high efficacy and good safety in seropositive persons in the 9-45 years age group, but a risk of severe dengue was observed in individuals who were naive for DENV infection at the time they were vaccinated.

abstract:
  A conference on «ARBOVIRUSES, A GLOBAL PUBLIC HEALTH THREAT» was organized on June 20–22, 2018 at the Merieux Foundation Conference Center in Veyrier du Lac, France, to review and raise awareness to the global public health threat of epidemic arboviruses, and to advance the discussion on the control and prevention of arboviral diseases. The presentations by scientists and public health officials from Asia, the Americas, Europe and Africa strengthened the notion that arboviral diseases of both humans and domestic animals are progressively becoming dominant public health problems in the world. The repeated occurrence of recent deadly epidemics strongly reinforces the call for action against these viral diseases, and the need for developing effective vaccines, drugs, vector control tools and strong prevention programs.


id: cord-273326-gmw8gl2r
title: Host-Directed Antivirals: A Realistic Alternative to Fight Zika Virus
author: Saiz, Juan-Carlos
date: 2018-08-24
txt: ./txt/cord-273326-gmw8gl2r.txt
cache: ./cache/cord-273326-gmw8gl2r.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/30149598/
doi: 10.3390/v10090453
summary:
  In this line, and contrary to above mentioned report [73] , CQ, an FDA-approved anti-inflammatory 4-aminoquinoline and an autophagy inhibitor widely used as an anti-malaria drug that is administered to pregnant women at risk of exposure to Plasmodium parasites, was shown to have anti-ZIKV activity in different cell types (Vero cells, human brain microvascular endothelial cells (hBMECs), and human neural stem cells (NSCs)), affecting early stages of the viral life cycle, possibly by raising the endosomal pH and inhibiting the fusion of the envelope protein to the endosomal membrane [74, 75] . Similarly, by using a drug repurposing screening of over 6000 molecules, it was found that emricasan, a pan-caspase inhibitor that restrains ZIKV-induced increases in caspase-3 activity and is currently in phase 2 clinical trials in chronic hepatitis C virus (HCV)-infected patients, protected human cortical neural progenitor cells (NPC) in both monolayer and three-dimensional organoid cultures, showing neuroprotective activity without suppression of viral replication [82] .

abstract:
  Zika virus (ZIKV), a mosquito-borne flavivirus, was an almost neglected pathogen until its introduction in the Americas in 2015, where it has been responsible for a threat to global health, causing a great social and sanitary alarm due to its increased virulence, rapid spread, and an association with severe neurological and ophthalmological complications. Currently, no specific antiviral therapy against ZIKV is available, and treatments are palliative and mainly directed toward the relief of symptoms, such as fever and rash, by administering antipyretics, anti-histamines, and fluids for dehydration. Nevertheless, lately, search for antivirals has been a major aim in ZIKV investigations. To do so, screening of libraries from different sources, testing of natural compounds, and repurposing of drugs with known antiviral activity have allowed the identification of several antiviral candidates directed to both viral (structural proteins and enzymes) and cellular elements. Here, we present an updated review of current knowledge about anti-ZIKV strategies, focusing on host-directed antivirals as a realistic alternative to combat ZIKV infection.


id: cord-278286-1xk31726
title: Basic insights into Zika virus infection of neuroglial and brain endothelial cells
author: Mutso, Margit
date: 2020-04-30
txt: ./txt/cord-278286-1xk31726.txt
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extension: .txt
mime: text/plain
url: https://doi.org/10.1099/jgv.0.001416
doi: 10.1099/jgv.0.001416
summary:
  This study characterizes the in vitro infection of laboratory-adapted ZIKV African MR766 and two Asian strains of (1) brain endothelial cells (hCMEC/D3 cell line) and (2) olfactory ensheathing cells (OECs) (the neuroglia populating cranial nerve I and the olfactory bulb; both human and mouse OEC lines) in comparison to kidney epithelial cells (Vero cells, in which ZIKV infection is well characterized). To characterize infection by different ZIKV strains (MR766, PRVABC59 and BeH819015), brain endothelial cells (hCMEC/D3) and neuroglial olfactory ensheathing cells (hOEC and mOEC) were infected at an m.o.i. of 0.1. To examine the virus persistence in neuroglia and human brain endothelial cell cultures, the viral RNA copy numbers in hCMEC/D3, hOEC and mOEC cells infected with MR766, PRVABC59 and BeH819015 for 2 months were quantified using RT-qPCR (Fig. 6) .

abstract:
  Zika virus (ZIKV) has recently emerged as an important human pathogen due to the strong evidence that it causes disease of the central nervous system, particularly microcephaly and Guillain–Barré syndrome. The pathogenesis of disease, including mechanisms of neuroinvasion, may include both invasion via the blood–brain barrier and via peripheral (including cranial) nerves. Cellular responses to infection are also poorly understood. This study characterizes the in vitro infection of laboratory-adapted ZIKV African MR766 and two Asian strains of (1) brain endothelial cells (hCMEC/D3 cell line) and (2) olfactory ensheathing cells (OECs) (the neuroglia populating cranial nerve I and the olfactory bulb; both human and mouse OEC lines) in comparison to kidney epithelial cells (Vero cells, in which ZIKV infection is well characterized). Readouts included infection kinetics, intracellular virus localization, viral persistence and cytokine responses. Although not as high as in Vero cells, viral titres exceeded 10(4) plaque-forming units (p.f.u.) ml(−1) in the endothelial/neuroglial cell types, except hOECs. Despite these substantial titres, a relatively small proportion of neuroglial cells were primarily infected. Immunolabelling of infected cells revealed localization of the ZIKV envelope and NS3 proteins in the cytoplasm; NS3 staining overlapped with that of dsRNA replication intermediate and the endoplasmic reticulum (ER). Infected OECs and endothelial cells produced high levels of pro-inflammatory chemokines. Nevertheless, ZIKV was also able to establish persistent infection in hOEC and hCMEC/D3 cells. Taken together, these results provide basic insights into ZIKV infection of endothelial and neuroglial cells and will form the basis for further study of ZIKV disease mechanisms.


id: cord-283405-aozxvxxs
title: Pregnancy and infection: using disease pathogenesis to inform vaccine strategy
author: Vermillion, Meghan S.
date: 2018-02-01
txt: ./txt/cord-283405-aozxvxxs.txt
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extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41541-017-0042-4
doi: 10.1038/s41541-017-0042-4
summary:
  Pregnant women, unborn fetuses, and neonates represent three populations of high-risk individuals that can all be simultaneously protected from vaccine-preventable infectious disease with strategic maternal immunization protocols. Third are neonatal and infant infections, which are not considered to pose significant risk to pregnant women or unborn fetuses, but can cause severe, and sometimes fatal disease in neonates and infants that lack protective maternal immunity following birth. Studies in pregnant nonhuman primates have been instrumental for the identification of CD4 + T cell responses as critical for early control of CMV infection and transmission during pregnancy, 100 and studies in guinea pigs have demonstrated that a single-cycle infectious CMV vaccine induces immune responses similar to natural infection and protects against congenital infection. 125 Vaccine candidates have been developed using diverse platforms, including DNA, mRNA, and purified inactivated and live-attenuated virus, many of which have been tested in non-pregnant mouse and nonhuman primate models for their ability to generate immune responses that mimic responses to natural infection and protected against ZIKV challenge.

abstract:
  Vaccination is the mainstay of preventative medicine for many infectious diseases. Pregnant women, unborn fetuses, and neonates represent three at-risk populations that can be simultaneously protected by strategic vaccination protocols. Because the pathogenesis of different infectious microbes varies based on tissue tropism, timing of infection, and host susceptibility, the goals of immunization are not uniform across all vaccines. Mechanistic understanding of infectious disease pathogenesis and immune responses is therefore essential to inform vaccine design and the implementation of appropriate immunization protocols that optimize protection of pregnant women, fetuses, and neonates.


id: cord-284646-fhruiw23
author: Jaeger, Anna S.
date: 2020-05-24
txt: ./txt/cord-284646-fhruiw23.txt
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extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0042682220300921
doi: 10.1016/j.virol.2020.05.005
summary:
  Vector competence experiments showed that Ae. aegypti could transmit SPONV when 70 exposed to bloodmeal titers that approximate physiological titers, while Cx. quinquefasciatus nonpregnant, mixed sex 6-to 11-week-old mice lacking type I interferon signaling (Ifnar1 -/-) Ar94 (this is the only strain used in these studies, so it will be referred to hereafter as 86 SPONV); or 10 2 PFU of the highly pathogenic African-lineage ZIKV strain DAK AR 41524 87 (ZIKV-DAK) (Jaeger et al., 2019) . Despite significantly higher maternal 141 viremia observed at 4 dpi with ZIKV-DAK-infected dams, the fact that resorption rates did 142 not significantly differ between the two groups indicates that both ZIKV-DAK and SPONV 143 have a propensity to harm the developing fetus that is independent of the amount of 144 replication in maternal blood. In contrast, ZIKV-DAK-and SPONV-inoculated dams displayed 221 varying degrees of placental pathology with severe effects predominantly observed in the 222 the labyrinth zone, including vascular injury involving maternal and/or fetal vascular spaces, 223 infarction (obstructed blood flow), necrosis, apoptosis, and hemorrhage (Fig. 4) .

title:
  Spondweni virus causes fetal harm in Ifnar1(-/-) mice and is transmitted by Aedes aegypti mosquitoes

abstract:
  Spondweni virus (SPONV) is the most closely related known flavivirus to Zika virus (ZIKV). Its pathogenic potential and vector specificity have not been well defined. SPONV has been found predominantly in Africa, but was recently detected in a pool of Culex quinquefasciatus mosquitoes in Haiti. Here we show that SPONV can cause significant fetal harm, including demise, comparable to ZIKV, in a mouse model of vertical transmission. Following maternal inoculation, we detected infectious SPONV in placentas and fetuses, along with significant fetal and placental histopathology, together suggesting vertical transmission. To test vector competence, we exposed Aedes aegypti and Culex quinquefasciatus mosquitoes to SPONV-infected bloodmeals. Aedes aegypti could efficiently transmit SPONV, whereas Culex quinquefasciatus could not. Our results suggest that SPONV has the same features that made ZIKV a public health risk.


id: cord-290385-0smnl70i
title: Zika fever and congenital Zika syndrome: An unexpected emerging arboviral disease
author: Chan, Jasper F.W.
date: 2016-03-03
txt: ./txt/cord-290385-0smnl70i.txt
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mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S016344531600061X
doi: 10.1016/j.jinf.2016.02.011
summary:
  Unlike its mosquito-borne relatives, such as dengue, West Nile, and Japanese encephalitis viruses, which can cause severe human diseases, Zika virus (ZIKV) has emerged from obscurity by its association with a suspected "congenital Zika syndrome", while causing asymptomatic or mild exanthematous febrile infections which are dengueor rubella-like in infected individuals. ZIKV RNA could be detected in breast milk and saliva of infected women, although replicative virus particles have not been demonstrated 78, 79 Perinatal transmission of other arboviruses, including DENV, CHIKV, WNV, and YFV, has also been reported. 115,120 74/ 8750 (0.8%) patients with suspected ZIKV infection in the French Polynesia outbreak developed neurological syndromes after presenting with a Zika fever-like illness. Zika fever-related death appears to be extremely rare but a number of probable cases have been reported, especially among immunocompromised patients and neonates with suspected congenital ZIKV infection.

abstract:
  Unlike its mosquito-borne relatives, such as dengue, West Nile, and Japanese encephalitis viruses, which can cause severe human diseases, Zika virus (ZIKV) has emerged from obscurity by its association with a suspected “congenital Zika syndrome”, while causing asymptomatic or mild exanthematous febrile infections which are dengue- or rubella-like in infected individuals. Despite having been discovered in Uganda for almost 60 years, <20 human cases were reported before 2007. The massive epidemics in the Pacific islands associated with the ZIKV Asian lineage in 2007 and 2013 were followed by explosive outbreaks in Latin America in 2015. Although increased mosquito breeding associated with the El Niño effect superimposed on global warming is suspected, genetic changes in its RNA virus genome may have led to better adaptation to mosquitoes, other animal reservoirs, and human. We reviewed the epidemiology, clinical manifestation, virology, pathogenesis, laboratory diagnosis, management, and prevention of this emerging infection. Laboratory diagnosis can be confounded by cross-reactivity with other circulating flaviviruses. Besides mosquito bite and transplacental transmission, the risk of other potential routes of transmission by transfusion, transplantation, sexual activity, breastfeeding, respiratory droplet, and animal bite is discussed. Epidemic control requires adequate clearance of mosquito breeding grounds, personal protection against mosquito bite, and hopefully a safe and effective vaccine.


id: cord-292830-gcfx1095
title: Novel activities of safe-in-human broad-spectrum antiviral agents
author: Ianevski, Aleksandr
date: 2018-04-23
txt: ./txt/cord-292830-gcfx1095.txt
cache: ./cache/cord-292830-gcfx1095.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/29698664/
doi: 10.1016/j.antiviral.2018.04.016
summary:
  Here, we reviewed all approved, investigational and experimental antiviral agents, which are safe in man, and identified 59 compounds that target at least three viral diseases. Here, we hypothesised that some of the identified safe-in-human BSAs could possess novel antiviral activities and, therefore, could be used for treatment of many different viral infections. Fig. 1 shows BSAs and other approved antiviral drugs linked to viral and host targets through viruses they inhibit. Thus, we tested several known BSA agents against (−)ssRNA, (+) ssRNA, ssRNA-RT and dsDNA viruses and identified novel activities for dalbavancin against EV1, ezetimibe against ZIKV and HIV-1, as well as azacitidine, cyclosporine, minocycline, oritavancin and ritonavir against RVFV. We identified novel antiviral activities for dalbavancin (against EV1), ezetimibe (against HIV-1 and ZIKV), azacitidine, cyclosporine, minocycline, oritavancin and ritonavir (against RVFV) (Fig. 4) .

abstract:
  According to the WHO, there is an urgent need for better control of viral diseases. Re-positioning existing safe-in-human antiviral agents from one viral disease to another could play a pivotal role in this process. Here, we reviewed all approved, investigational and experimental antiviral agents, which are safe in man, and identified 59 compounds that target at least three viral diseases. We tested 55 of these compounds against eight different RNA and DNA viruses. We found novel activities for dalbavancin against echovirus 1, ezetimibe against human immunodeficiency virus 1 and Zika virus, as well as azacitidine, cyclosporine, minocycline, oritavancin and ritonavir against Rift valley fever virus. Thus, the spectrum of antiviral activities of existing antiviral agents could be expanded towards other viral diseases.


id: cord-294798-ji3p0l4j
author: White, Sarah K.
date: 2018-05-31
txt: ./txt/cord-294798-ji3p0l4j.txt
cache: ./cache/cord-294798-ji3p0l4j.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1371/journal.pntd.0006505
doi: 10.1371/journal.pntd.0006505
summary:
  We have previously reported isolation of ZIKV [8] , DENV [9] , Human coronavirus NL63 [10] , and Enterovirus D68 [11] from children in this school cohort; however, the cases/outbreaks in these prior publications did not include CHIKV, or cases within the May-August, 2014, time frame of the current study. Viral genomic RNA that was extracted from CHIKV, DENV1-4, and ZIKV strains that were obtained from the Biodefense and Emerging Infections Research Resource Repository (BEI Resources, Manassas, VA) were used as positive control materials for rtRT-PCR. The six ZIKV sequences obtained in June 2014 from the CHIKV co-infected patients were highly similar (99.9%) to each other and also cluster within a well-supported monophyletic clade, which, interestingly, includes a divergent strain isolated in 2016 from Guadaloupe (Figs 3B and S3B) .

title:
  Detection and phylogenetic characterization of arbovirus dual-infections among persons during a chikungunya fever outbreak, Haiti 2014

abstract:
  In the context of recent arbovirus epidemics, questions about the frequency of simultaneous infection of patients with different arbovirus species have been raised. In 2014, a major Chikungunya virus (CHIKV) epidemic impacted the Caribbean and South America. As part of ongoing screening of schoolchildren presenting with acute undifferentiated febrile illness in rural Haiti, we used RT-PCR to identify CHIKV infections in 82 of 100 children with this diagnosis during May—August 2014. Among these, eight were infected with a second arbovirus: six with Zika virus (ZIKV), one with Dengue virus serotype 2, and one with Mayaro virus (MAYV). These dual infections were only detected following culture of the specimen, suggesting low viral loads of the co-infecting species. Phylogenetic analyses indicated that the ZIKV and MAYV strains differ from those detected later in 2014 and 2015, respectively. Moreover, CHIKV and ZIKV strains from co-infected patients clustered monophyletically in their respective phylogeny, and clock calibration traced back the common ancestor of each clade to an overlapping timeframe of introduction of these arboviruses onto the island.


id: cord-295351-0zr2e8lh
title: Endoplasmic reticulum: a focal point of Zika virus infection
author: Mohd Ropidi, Muhammad Izzuddin
date: 2020-01-20
txt: ./txt/cord-295351-0zr2e8lh.txt
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extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/31959174/
doi: 10.1186/s12929-020-0618-6
summary:
  Following ZIKV infection, the accumulation of misfolded virus polyproteins in the ER lumen overwhelms the ER protein-folding capacity leading to ER stress and triggers the activation of the UPR (Fig. 2) [47] . Following the dissociation of GRP78 that unmasks the GLS, ATF6 translocate to the Golgi apparatus and undergoes sequential proteolytic processing by Fig. 2 ZIKV-induced ER stress initiates host cell unfolded protein response (UPR). ZIKV infection induces ER stress due to the increased amount of unfolded/misfolded viral (red strand) and host cell (grey strand) protein aggregates in the ER lumen. To summarize, ZIKV virus bypasses the UPR by inhibiting stress granules assembly and reticulophagy to ensure continuous viral protein translation and virion production while simultaneously protecting the virus from host cell defense mechanisms.

abstract:
  Zika virus (ZIKV) belongs to the Flavivirus genus of the Flaviviridae family. It is an arbovirus that can cause congenital abnormalities and is sexually transmissible. A series of outbreaks accompanied by unexpected severe clinical complications have captured medical attention to further characterize the clinical features of congenital ZIKV syndrome and its underlying pathophysiological mechanisms. Endoplasmic reticulum (ER) and ER-related proteins are essential in ZIKV genome replication. This review highlights the subcellular localization of ZIKV to the ER and ZIKV modulation on the architecture of the ER. This review also discusses ZIKV interaction with ER proteins such as signal peptidase complex subunit 1 (SPCS1), ER membrane complex (EMC) subunits, and ER translocon for viral replication. Furthermore, the review covers several important resulting effects of ZIKV infection to the ER and cellular processes including ER stress, reticulophagy, and paraptosis-like death. Pharmacological targeting of ZIKV-affected ER-resident proteins and ER-associated components demonstrate promising signs of combating ZIKV infection and rescuing host organisms from severe neurologic sequelae.


id: cord-298166-045evk7g
title: The molecular tweezer CLR01 inhibits Ebola and Zika virus infection
author: Röcker, Annika E.
date: 2018-02-08
txt: ./txt/cord-298166-045evk7g.txt
cache: ./cache/cord-298166-045evk7g.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0166354217308458
doi: 10.1016/j.antiviral.2018.02.003
summary:
  As no preventive vaccines or antiviral drugs against these two re-emerging pathogens are available, we evaluated whether the molecular tweezer CLR01 may inhibit EBOV and ZIKV infection. The tweezer inhibited infection of epidemic ZIKV strains in cells derived from the anogenital tract and the central nervous system, and remained antivirally active in the presence of semen, saliva, urine and cerebrospinal fluid. Methods describing the effect of CLR01 on pseudotyped lentiviral particles (2.3.), Ebola virus infection (2.4.), the detection of ZIKV infection by a colorimetric MTT assay (2.5.) or by cell-based ZIKV immunodetection assay (2.6.), flow cytometry (2.7.) and confocal microscopy (2.8.) as well as the RNA release assay (2.9.) and the antiviral activity of CLR01 in body fluids (2.10) can be found in the supplement.

abstract:
  Ebola (EBOV) and Zika viruses (ZIKV) are responsible for recent global health threats. As no preventive vaccines or antiviral drugs against these two re-emerging pathogens are available, we evaluated whether the molecular tweezer CLR01 may inhibit EBOV and ZIKV infection. This small molecule has previously been shown to inactivate HIV-1 and herpes viruses through a selective interaction with lipid-raft-rich regions in the viral envelope, which results in membrane disruption and loss of infectivity. We found that CLR01 indeed blocked infection of EBOV and ZIKV in a dose-dependent manner. The tweezer inhibited infection of epidemic ZIKV strains in cells derived from the anogenital tract and the central nervous system, and remained antivirally active in the presence of semen, saliva, urine and cerebrospinal fluid. Our findings show that CLR01 is a broad-spectrum inhibitor of enveloped viruses with prospects as a preventative microbicide or antiviral agent.


id: cord-300379-db79kb5c
title: Potent Inhibition of Zika Virus Replication by Aurintricarboxylic Acid
author: Park, Jun-Gyu
date: 2019-04-12
txt: ./txt/cord-300379-db79kb5c.txt
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extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/31031722/
doi: 10.3389/fmicb.2019.00718
summary:
  To quantify the ability of ATA to prevent ZIKV-induced apoptosis, tissue culture supernatants from ZIKV-infected Vero and A549 cells were harvested at 24, 48, and 72 h p.i. to measure the level of apoptotic signal as determined by caspase 3 and 7 activities ( Figure 5B) . ZIKV-infected cells showed FIGURE 4 | Aurintricarboxylic acid inhibition of ZIKV replication: Vero (A) and A549 (B) cells (24-well plate format, 2.5 × 10 5 cells/well, triplicates) were infected (MOI 0.1) with Paraiba/2015. In this study, we demonstrated that ATA (Figure 1 ) has limited toxicity (Figure 2) and an effective and dose-dependent antiviral activity against ZIKV infection (Figures 3, 4) in both monkey kidney epithelial Vero and human alveolar A549 cells. Notably, ATA can prevent ZIKV-induced CPE and apoptosis in both cell lines ( Figure 5 ) and has broad anti-viral activity against representative ZIKV strains from the African (Uganda/1947 and Nigeria/1968) and the Asian/American (Puerto Rico/2015 and French Polynesia/2013) lineages (Figure 6) .

abstract:
  Zika virus (ZIKV) is one of the recently emerging vector-borne viruses in humans and is responsible for severe congenital abnormalities such as microcephaly in the Western Hemisphere. Currently, only a few vaccine candidates and therapeutic drugs are being developed for the treatment of ZIKV infections, and as of yet none are commercially available. The polyanionic aromatic compound aurintricarboxylic acid (ATA) has been shown to have a broad-spectrum antimicrobial and antiviral activity. In this study, we evaluated ATA as a potential antiviral drug against ZIKV replication. The antiviral activity of ATA against ZIKV replication in vitro showed median inhibitory concentrations (IC(50)) of 13.87 ± 1.09 μM and 33.33 ± 1.13 μM in Vero and A549 cells, respectively; without showing any cytotoxic effect in both cell lines (median cytotoxic concentration (CC(50)) > 1,000 μM). Moreover, ATA protected both cell types from ZIKV-induced cytopathic effect (CPE) and apoptosis in a time- and concentration-dependent manner. In addition, pre-treatment of Vero cells with ATA for up to 72 h also resulted in effective suppression of ZIKV replication with similar IC(50). Importantly, the inhibitory effect of ATA on ZIKV infection was effective against strains of the African and Asian/American lineages, indicating that this inhibitory effect was not strain dependent. Overall, these results demonstrate that ATA has potent inhibitory activity against ZIKV replication and may be considered as a potential anti-ZIKV therapy for future clinical evaluation.


id: cord-300459-tu2xrt9x
author: Li, Cui
date: 2018-05-01
txt: ./txt/cord-300459-tu2xrt9x.txt
cache: ./cache/cord-300459-tu2xrt9x.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S2211124718305345
doi: 10.1016/j.celrep.2018.04.005
summary:
  We previously reported on a panel of monoclonal antibodies (mAbs) derived from the longitudinal samples of a ZIKV-convalescent individual and characterized their neutralizing activities, epitope specificities, and development timeline over the course of infection . Here, we use the mouse models of ZIKV infection and microcephaly to analyze the in vivo protective activities of six human mAbs and compare the findings with our reported in vitro neutralization activity, as measured by plaque reduction neutralization test (PRNT). mAbs that target DIII with potent neutralizing activity have also been isolated by other groups, derived from either infected humans or mice, and have been shown to be effective in various models of ZIKV pathogenesis (Fernandez et al., 2017; Magnani et al., 2017; Robbiani et al., 2017; Stettler et al., 2016; Wang et al., 2017b; Zhao et al., 2016) .

title:
  A Single Injection of Human Neutralizing Antibody Protects against Zika Virus Infection and Microcephaly in Developing Mouse Embryos

abstract:
  Zika virus (ZIKV) is a mosquito-transmitted flavivirus that is generally benign in humans. However, an emergent strain of ZIKV has become widespread, causing severe pre- and post-natal neurological defects. There is now an urgent need for prophylactic and therapeutic agents. To address this, we investigated six human monoclonal antibodies with ZIKV epitope specificity and neutralizing activity in mouse models of ZIKV infection and microcephaly. A single intraperitoneal injection of these antibodies conveyed distinct levels of adult and in utero protection from ZIKV infection, which closely mirrored their respective in vitro neutralizing activities. One antibody, ZK2B10, showed the most potent neutralization activity, completely protected uninfected mice, and markedly reduced tissue pathology in infected mice. Thus, ZK2B10 is a promising candidate for the development of antibody-based interventions and informs the rational design of ZIKV vaccine.


id: cord-309275-soffxxqu
title: DEFA1B inhibits ZIKV replication and retards cell cycle progression through interaction with ORC1
author: Li, Shuang
date: 2020-10-17
txt: ./txt/cord-309275-soffxxqu.txt
cache: ./cache/cord-309275-soffxxqu.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0024320520313175?v=s5
doi: 10.1016/j.lfs.2020.118564
summary:
  title: DEFA1B inhibits ZIKV replication and retards cell cycle progression through interaction with ORC1 KEY FINDINGS: Through human transcriptome array (HTA) we found the defensin alpha 1B (DEFA1B) expression was significantly increased within exosomes isolated from ZIKV infected A549 cells. Further studies demonstrated that DEFA1B interacted with the origin recognition complex 1 (ORC1) which is required to initiate DNA replication during the cell cycle and increased DEFA1B expression decreased the ORC1 level in the cell nuclei. SIGNIFICANCE: Together, our results demonstrated that the anti-ZIKV activity of DEFA1B can be mediated by exosomes, and DEFA1B interacts with ORC1 to retard cell cycles. Both qPCR ( Figure 3K ) and western blot ( Figure 3L ) data showed no significant changes of ZIKV replication between untreated HEK293T cells and cells with up-regulated DEFA1B group. Our data showed the ZIKV induced exosomes could be internalized into recipient cells and inhibit the cells'' DNA replication to retard cell cycles.

abstract:
  AIMS: Zika virus (ZIKV) infection causes a public health concern because of its potential association with the development of microcephaly. During viral infections, the host innate immune response is mounted quickly to produce some endogenous functional molecules to limit virus replication and spread. Exosomes contain molecules from their cell of origin following virus infection and can enter recipient cells for intercellular communication. Here, we aim to clarify whether ZIKV-induced exosomes can regulate viral pathogenicity by transferring specific RNAs. MAIN METHODS: In this study, exosomes were isolated from the supernatants of A549 cells with or without ZIKV infection. Human transcriptome array (HTA) was performed to analyze the profiling of RNAs wrapped in exosomes. Then qPCR, western blotting and ELISA were used to determine ZIKV replication. CCK-8 and flow cytometry were used to test the cell proliferation and cell cycles. Co-culture assay was used to analyze the effect of exosomes on the cell cycles of recipient cells. KEY FINDINGS: Through human transcriptome array (HTA) we found the defensin alpha 1B (DEFA1B) expression was significantly increased within exosomes isolated from ZIKV infected A549 cells. Additionally, we found that the extracellular DEFA1B exerts significant anti-ZIKV activity, mainly before ZIKV entering host cells. Interestingly, up-regulated DEFA1B retards the cell cycle of host cells. Further studies demonstrated that DEFA1B interacted with the origin recognition complex 1 (ORC1) which is required to initiate DNA replication during the cell cycle and increased DEFA1B expression decreased the ORC1 level in the cell nuclei. Accordingly, DEFA1B-containing exosomes can be internalized by the recipient cells to retard their cell cycles. SIGNIFICANCE: Together, our results demonstrated that the anti-ZIKV activity of DEFA1B can be mediated by exosomes, and DEFA1B interacts with ORC1 to retard cell cycles. Our study provides a novel concept that DEFA1B not only acts as an antiviral molecule during ZIKV infection but also may correlate with cell proliferation by retarding the progression of cell cycles.


id: cord-310004-h9ixhhzz
author: Yuan, Shuofeng
date: 2020-08-28
txt: ./txt/cord-310004-h9ixhhzz.txt
cache: ./cache/cord-310004-h9ixhhzz.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32923629/
doi: 10.1126/sciadv.aba7910
summary:
  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. To prioritize these five compounds, we evaluated their antiviral efficacy against other emerging viruses and identified ACA as the only inhibitor that exhibited a broad-spectrum antiviral effect against influenza A H1N1, ZIKV, HIV-1, SARS-CoV-2, EV-A71, human adenovirus 5 (AdV5), and severe fever with thrombocytopenia syndrome virus (SFTSV) (Fig. 1C and fig. Using our previously established proximal differentiated threedimensional (3D) human airway organoids (AOs) for predicting the infectivity of influenza viruses in humans (14) , we confirmed that ACA reduced virus replication by >4 logs (Fig. 2D) , with markedly decreased expression of viral nucleoprotein (NP) antigen (Fig. 2E) .

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-311007-0i1abjfa
title: Rescue of the 1947 Zika Virus Prototype Strain with a Cytomegalovirus Promoter-Driven cDNA Clone
author: Schwarz, Megan C.
date: 2016-09-28
txt: ./txt/cord-311007-0i1abjfa.txt
cache: ./cache/cord-311007-0i1abjfa.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/27704051/
doi: 10.1128/msphere.00246-16
summary:
  High levels of infectious virus were produced following transfection of the plasmid bearing the wild-type MR766 ZIKV genome, but not one with a disruption to the viral nonstructural protein 5 (NS5) polymerase active site. Multicycle growth curve and plaque assay experiments indicated that the MR766 virus resulting from plasmid transfection exhibited growth characteristics that were more similar to its parental isolate than previously published 2010 Cambodia and 2015 Brazil cDNA-rescued ZIKV. Indeed, sequence analysis of bacterial plasmid clones of these RT-PCRs demonstrated that all products from wild-type plasmid-transfected cell RNA lacked the inserted intron (Fig. 3B) . In contrast to parental virus RT-PCR products (Fig. 3B) , these sequences carried a single silent G3127A mutation that was inserted during intron cloning, which indicated that these RNAs were generated from the MR766 plasmid. The addition of supernatants from wild-type plasmid-transfected or parental virus-infected 293T cells resulted in readily detectable levels of viral proteins.

abstract:
  The recent Zika virus (ZIKV) outbreak has been linked to severe pathogenesis. Here, we report the construction of a plasmid carrying a cytomegalovirus (CMV) promoter-expressed prototype 1947 Uganda MR766 ZIKV cDNA that can initiate infection following direct plasmid DNA transfection of mammalian cells. Incorporation of a synthetic intron in the nonstructural protein 1 (NS1) region of the ZIKV polyprotein reduced viral cDNA-associated toxicity in bacteria. High levels of infectious virus were produced following transfection of the plasmid bearing the wild-type MR766 ZIKV genome, but not one with a disruption to the viral nonstructural protein 5 (NS5) polymerase active site. Multicycle growth curve and plaque assay experiments indicated that the MR766 virus resulting from plasmid transfection exhibited growth characteristics that were more similar to its parental isolate than previously published 2010 Cambodia and 2015 Brazil cDNA-rescued ZIKV. This ZIKV infectious clone will be useful for investigating the genetic determinants of ZIKV infection and pathogenesis and should be amenable to construction of diverse infectious clones expressing reporter proteins and representing a range of ZIKV isolates. IMPORTANCE The study of ZIKV, which has become increasingly important with the recent association of this virus with microcephaly and Guillain-Barré syndrome, would benefit from an efficient strategy to genetically manipulate the virus. This work describes a model system to produce infectious virus in cell culture. We created a plasmid carrying the prototype 1947 Uganda MR766 ZIKV genome that both was stable in bacteria and could produce high levels of infectious virus in mammalian cells through direct delivery of this DNA. Furthermore, growth properties of this rescued virus closely resembled those of the viral isolate from which it was derived. This model system will provide a simple and effective means to study how ZIKV genetics impact viral replication and pathogenesis.


id: cord-319781-6thdg2up
author: Payne, Kelly
date: 2020-07-24
txt: ./txt/cord-319781-6thdg2up.txt
cache: ./cache/cord-319781-6thdg2up.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.sxmr.2020.06.003
doi: 10.1016/j.sxmr.2020.06.003
summary:
  To understand factors that may contribute to viral spread and address long-term health sequelae for survivors, it is important to review evidence regarding viral presence in semen, sexual transmission potential, and possible effects on fertility. We review evidence for the following viruses: Ebola, Zika, West Nile, pandemic influenza, severe acute respiratory syndrome (SARS), and SARS-corona virus-2 (SARS-CoV-2). Then, we present the state of current research regarding presence in semen, sexual transmission, and fertility effects for the Zika virus (ZIKV), Ebola virus (EBOV), West Nile virus (WNV), pandemic influenza, severe acute respiratory syndrome (SARS), and SARS-coronavirus-2 (SARS-CoV-2) ( Table 1) . In this article, we have reviewed the presence in semen, possibility of sexual transmission, and fertility implications of each of the major recent viral pandemics: Zika, Ebola, West Nile, pandemic influenza, SARS, and SARS-CoV-2.

title:
  Twenty-First Century Viral Pandemics: A Literature Review of Sexual Transmission and Fertility Implications in Men

abstract:
  INTRODUCTION: The 21st century has seen a series of viral pandemics that have collectively infected millions of individuals. To understand factors that may contribute to viral spread and address long-term health sequelae for survivors, it is important to review evidence regarding viral presence in semen, sexual transmission potential, and possible effects on fertility. AIM: To review the current literature regarding the sexual transmissibility of recent viral pandemics and their effects on semen parameters and fertility. We review evidence for the following viruses: Ebola, Zika, West Nile, pandemic influenza, severe acute respiratory syndrome (SARS), and SARS-corona virus-2 (SARS-CoV-2). METHODS: A literature search was conducted to identify relevant studies. Titles and abstracts were reviewed for relevance. References from identified articles were searched and included, if appropriate. MAIN OUTCOME MEASURES: The main outcome measure of this study was reviewing of peer-reviewed literature. RESULTS: Both the Ebola virus and Zika virus are present in semen, but only the Zika virus shows consistent evidence of sexual transmission. Current evidence does not support the presence of the West Nile virus, pandemic influenza, SARS, and SARS-CoV-2 in semen. The Zika virus appears to alter semen parameters in a way that diminishes fertility, but the effect is likely time limited. The West Nile virus and SARS have been associated with orchitis in a small number of case reports. Viruses that cause febrile illness, such as pandemic influenza, SARS, and SARS-CoV-2, are associated with decreased sperm count and motility and abnormal morphology. SARS and SARS-CoV-2 may interact with angiotensin-converting enzyme 2 receptors present in the testes, which could impact spermatogenesis. CONCLUSIONS: We have reported the presence in semen, sexual transmission potential, and fertility side effects of recent viral pandemics. Overall, semen studies and fertility effects are highly understudied in viral pandemics, and rigorous study on these topics should be undertaken as novel pandemics emerge. Payne K, Kenny P, Scovell JM, et al. Twenty-First Century Viral Pandemics: A Literature Review of Sexual Transmission and Fertility Implications for Men. Sex Med Rev 2020;XX:XXX–XXX.


id: cord-321312-hgp2jwbl
author: Carvalho, Sandhra M.
date: 2020-07-10
txt: ./txt/cord-321312-hgp2jwbl.txt
cache: ./cache/cord-321312-hgp2jwbl.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0167577X20309848?v=s5
doi: 10.1016/j.matlet.2020.128279
summary:
  title: Fluorescent Quantum Dots-Zika Virus Hybrid Nanoconjugates for Biolabeling, Bioimaging, and Tracking Host-Cell Interactions Thus, we designed and developed for the first time, novel bioconjugates made of Ag-In-S@ZnS (ZAIS) fluorescent quantum dots coupled with ZIKA virus via covalent amide bond with carboxymethylcellulose (CMC) biopolymer for labeling and bioimaging the virus-host cell interactions mechanisms through confocal laser scanning microscopy. This work offers relevant insights regarding the profile of the ZIKA virus-nanoparticle conjugates interactions with VERO cells, which can be applied as a nanoplatform to elucidate the infection mechanisms caused by this viral disease. For biolabeling and bioimaging virus-host cell interactions in vitro, ZIKV_ZAIS conjugates were incubated with VERO cells. The QDs conjugated with ZIKV presented higher entry to VERO cells in comparison to reference QD (ZAIS), indicating the possibility of labeling and detection of ZIKV for tracking the viral infection processes including virus entry and transport in cells. ZAIS-CMC fluorescent conjugates showed insights of ZIKA virus-host cell interactions

title:
  Fluorescent Quantum Dots-Zika Virus Hybrid Nanoconjugates for Biolabeling, Bioimaging, and Tracking Host-Cell Interactions

abstract:
  The earliest possible diagnosis and understanding of the infection mechanisms play a crucial role in the outcome of fighting viral diseases. Thus, we designed and developed for the first time, novel bioconjugates made of Ag-In-S@ZnS (ZAIS) fluorescent quantum dots coupled with ZIKA virus via covalent amide bond with carboxymethylcellulose (CMC) biopolymer for labeling and bioimaging the virus-host cell interactions mechanisms through confocal laser scanning microscopy. This work offers relevant insights regarding the profile of the ZIKA virus-nanoparticle conjugates interactions with VERO cells, which can be applied as a nanoplatform to elucidate the infection mechanisms caused by this viral disease.


id: cord-326512-iex98lr1
author: Niu, Xuefeng
date: 2019-05-25
txt: ./txt/cord-326512-iex98lr1.txt
cache: ./cache/cord-326512-iex98lr1.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/31130109/
doi: 10.1080/22221751.2019.1614885
summary:
  title: Convalescent patient-derived monoclonal antibodies targeting different epitopes of E protein confer protection against Zika virus in a neonatal mouse model To examine antibody response in a patient infected with ZIKV, we used single-cell PCR to clone 31 heavy and light chain-paired monoclonal antibodies (mAbs) that bind to ZIKV envelope (E) proteins isolated from memory B cells of a ZIKV-infected patient. The SHM rates of these heavy chains compared with their predicted germline sequences were relatively low, at 4.51% for 7B3H, 3.47% for 1C11H, and 4.17% for 6A6H, which is lower than that of antibodies isolated from annual trivalent inactivated influenza vaccine (TIV) donors [34] and chronic human immunodeficiency virus (HIV)-1 patients (>30%) [27, 35] . In a separate experiment, an unrelated mAb, 2G11, which is specific for H7N9 influenza virus, showed no protective effects on ZIKV-infected neonatal SCID mice (data not shown). Molecular determinants of human neutralizing antibodies isolated from a patient infected with Zika virus

title:
  Convalescent patient-derived monoclonal antibodies targeting different epitopes of E protein confer protection against Zika virus in a neonatal mouse model

abstract:
  The Zika virus (ZIKV) outbreak and its link to microcephaly triggered a public health concern. To examine antibody response in a patient infected with ZIKV, we used single-cell PCR to clone 31 heavy and light chain-paired monoclonal antibodies (mAbs) that bind to ZIKV envelope (E) proteins isolated from memory B cells of a ZIKV-infected patient. Three mAbs (7B3, 1C11, and 6A6) that showed the most potent and broad neutralization activities against the African, Asian, and American strains were selected for further analysis. mAb 7B3 showed an IC50 value of 11.6 ng/mL against the circulating American strain GZ02. Epitope mapping revealed that mAbs 7B3 and 1C11 targeted residue K394 of the lateral ridge (LR) epitope of the EDIII domain, but 7B3 has a broader LR epitope footprint and recognizes residues T335, G337, E370, and N371 as well. mAb 6A6 recognized residues D67, K118, and K251 of the EDII domain. Interestingly, although the patient was seronegative for DENV infection, mAb 1C11, originating from the VH3-23 and VK1-5 germline pair, neutralized both ZIKV and DENV1. Administration of the mAbs 7B3, 1C11, and 6A6 protected neonatal SCID mice infected with a lethal dose of ZIKV. This study provides potential therapeutic antibody candidates and insights into the antibody response after ZIKV infection.


id: cord-330743-o11d0aa1
author: Yu, Xi
date: 2020-05-25
txt: ./txt/cord-330743-o11d0aa1.txt
cache: ./cache/cord-330743-o11d0aa1.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.05.22.109900
doi: 10.1101/2020.05.22.109900
summary:
  Herein, we identified 2 secreted bacterial lipases from a Chromobacterium bacterium, named Chromobacterium antiviral effector-1 (CbAE-1) and CbAE-2, with a broad-spectrum virucidal activity against dengue virus (DENV), Zika virus (ZIKV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human immunodeficiency virus (HIV) and herpes simplex virus (HSV). Incubation of the culture supernatant but not the bacterial lysates resulted in significant suppression of DENV ( Figure 1B ) and ZIKV ( Figure 1C ) infectivity in Vero cells, indicating that an extracellular effector(s) secreted by Csp_BJ was responsible for viral inhibition. DENV, ZIKV, HSV-1 and SARS-CoV-2 virus stocks were diluted to 50 plaque-forming units (pfu) per ml and incubated untreated or with a serial dilution of the CbAEs in five-fold steps at 37°C for 1 hr before being added onto Vero cell monolayers for 2 hr of infection.

title:
  Broad-spectrum virucidal activity of bacterial secreted lipases against flaviviruses, SARS-CoV-2 and other enveloped viruses

abstract:
  Viruses are the major aetiological agents of acute and chronic severe human diseases that place a tremendous burden on global public health and economy; however, for most viruses, effective prophylactics and therapeutics are lacking, in particular, broad-spectrum antiviral agents. Herein, we identified 2 secreted bacterial lipases from a Chromobacterium bacterium, named Chromobacterium antiviral effector-1 (CbAE-1) and CbAE-2, with a broad-spectrum virucidal activity against dengue virus (DENV), Zika virus (ZIKV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human immunodeficiency virus (HIV) and herpes simplex virus (HSV). The CbAEs potently blocked viral infection in the extracellular milieu through their lipase activity. Mechanistic studies showed that this lipase activity directly disrupted the viral envelope structure, thus inactivating infectivity. A mutation of CbAE-1 in its lipase motif fully abrogated the virucidal ability. Furthermore, CbAE-2 presented low toxicity in vivo and in vitro, highlighting its potential as a broad-spectrum antiviral drug.


id: cord-332473-ec8lu2a3
title: Zika virus inhibits eIF2α-dependent stress granule assembly
author: Amorim, Raquel
date: 2017-07-17
txt: ./txt/cord-332473-ec8lu2a3.txt
cache: ./cache/cord-332473-ec8lu2a3.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/28715409/
doi: 10.1371/journal.pntd.0005775
summary:
  In cells treated with salubrinal prior to Ars-induced stress, ZIKV-infected cells present higher levels of phospho-eIF2α as compared to mock-infected control (Fig 6C, compare lanes 6 and 8) . Zika virus inhibits stress granule assembly treated mock-infected cells (Fig 6E) . C. Vero cells were infected with ZIKV or mock-infected and treated at 24 hpi with 75 μM salubrinal for 3 h to block the dephosphorylation of eIF2α and then treated with 500 μM Ars for 1 h to induce cellular stress. D. Vero cells were infected with ZIKV or mock-infected and at 24 hpi were treated with 75 μM salubrinal for 3 h and then oxidative stress was induced by treatment with 500 μM Ars for 1 h. Vero cells were infected with ZIKV or mock-infected and treated at 24 hpi with 10 μM sal003 for 3 h to block the dephosphorylation of eIF2α and then treated with 500 μM Ars for 1 h to induce cellular stress.

abstract:
  Zika virus (ZIKV), a member of the Flaviviridae family, is the most recent emerging arbovirus with pandemic potential. During infection, viruses trigger the host cell stress response, leading to changes in RNA translation and the assembly of large aggregates of stalled translation preinitiation complexes, termed stress granules (SGs). Several reports demonstrate that flaviviruses modulate the assembly of stress granules (SG). As an emerging pathogen, little is known however about how ZIKV modulates the host cell stress response. In this work, we investigate how ZIKV modulates SG assembly. We demonstrate that ZIKV negatively impacts SG assembly under oxidative stress conditions induced by sodium arsenite (Ars), a treatment that leads to the phosphorylation of eIF2α. By contrast, no measurable difference in SG assembly was observed between mock and ZIKV-infected cells treated with sodium selenite (Se) or Pateamine A (PatA), compounds that trigger eIF2α-independent SG assembly. Interestingly, ZIKV infection markedly impaired the phosphorylation of eIF2α triggered in Ars-treated infected cells, and the abrogation of SG assembly in ZIKV-infected cells is, at least in part, dependent on eIF2α dephosphorylation. These data demonstrate that ZIKV elicits mechanisms to counteract host anti-viral stress responses to promote a cellular environment propitious for viral replication.


id: cord-338136-nbtkl5cx
title: Geographies of risk: Emerging infectious diseases and travel health data
author: Clemente, Nuria Sanchez
date: 2020-06-25
txt: ./txt/cord-338136-nbtkl5cx.txt
cache: ./cache/cord-338136-nbtkl5cx.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.tmaid.2020.101806
doi: 10.1016/j.tmaid.2020.101806
abstract: nan
summary:
  Reflecting on the findings of Petridou and colleagues, 1 describing imported ZIKV cases to the UK between 2016-2018, confirmed at the Rare and Imported Pathogens Laboratory, we look back to the 2015-2017 Zika virus (ZIKV) pandemic and reflect on some of the opportunities and limitations presented by data obtained from returning travellers in enhancing understanding of emerging infectious diseases. Given travellers'' well-defined temporal windows of potential exposure, improved recollections of risk behaviors, and access to well-resourced travel clinic laboratories, travel health data are uniquely positioned to provide insights into the pathogenesis of emergent infectious diseases. While travel health data has the opportunity to build on this foundation and provide novel insights about emerging infectious agents, the fastest progress will be made through meaningful bi-directional international partnerships built on respectful collaboration, commitments to capacity building, and cooperative efforts to bolster surveillance. Travel Medicine and Infectious Disease requires that all authors sign a declaration of conflicting interests. Travel Medicine and Infectious Disease requires that all authors sign a declaration of conflicting interests.


id: cord-340907-j9i1wlak
title: Evolutionary selection against short nucleotide sequences in viruses and their related hosts
author: Zarai, Yoram
date: 2020-04-27
txt: ./txt/cord-340907-j9i1wlak.txt
cache: ./cache/cord-340907-j9i1wlak.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32339222/
doi: 10.1093/dnares/dsaa008
summary:
  Here, based on a novel statistical framework and a large-scale genomic analysis of 2,625 viruses from all classes infecting 439 host organisms from all kingdoms of life, we identify short nucleotide sequences that are under-represented in the coding regions of viruses and their hosts. Figure 3A and B depicts the average number of under-represented sequences of size m ¼ 3, 4, and 5 nucleotides, identified in few subsets of viruses in both the original and random variants of the virus. A sampling analysis that we performed (see Supplementary document, Section 2.8) suggests that the number of under-represented sequences identified in dsDNA viruses matches their genomic size, when compared with RNA viruses. To show that the correspondence between selection against short palindromic sequences in viruses and restriction sites cannot be explained by basic coding region features such as amino-acid content and order, codon usage bias and dinucleotide distribution, we also evaluated the overlap between restriction sites and common under-represented sequences of random variants of viruses.

abstract:
  Viruses are under constant evolutionary pressure to effectively interact with the host intracellular factors, while evading its immune system. Understanding how viruses co-evolve with their hosts is a fundamental topic in molecular evolution and may also aid in developing novel viral based applications such as vaccines, oncologic therapies, and anti-bacterial treatments. Here, based on a novel statistical framework and a large-scale genomic analysis of 2,625 viruses from all classes infecting 439 host organisms from all kingdoms of life, we identify short nucleotide sequences that are under-represented in the coding regions of viruses and their hosts. These sequences cannot be explained by the coding regions’ amino acid content, codon, and dinucleotide frequencies. We specifically show that short homooligonucleotide and palindromic sequences tend to be under-represented in many viruses probably due to their effect on gene expression regulation and the interaction with the host immune system. In addition, we show that more sequences tend to be under-represented in dsDNA viruses than in other viral groups. Finally, we demonstrate, based on in vitro and in vivo experiments, how under-represented sequences can be used to attenuated Zika virus strains.


id: cord-341907-vql8e2j3
author: Wang, Xinyi
date: 2019-10-27
txt: ./txt/cord-341907-vql8e2j3.txt
cache: ./cache/cord-341907-vql8e2j3.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3390/vaccines7040161
doi: 10.3390/vaccines7040161
summary:
  Our data show that, although vaccine formulated with a single adjuvant induced a specific antibody and cellular immune response, and reduced viral load in mice challenged with ZIKV, the combination of Alum and MPL adjuvants led to a more robust and balanced immune response, stronger neutralizing activity against three recent ZIKV human strains, and greater protection against a high-dose ZIKV challenge. Nevertheless, when coating the ELISA plate with a ZIKV full-length E protein without hFc, significantly high-titer IgG antibodies were induced, particularly in the Alum and MPL-adjuvanted EDIII ( Figure 2C ), suggesting that fusion of hFc to the EDIII subunit vaccine did not affect the generation of ZIKV-specific IgG antibodies. Nevertheless, when coating the ELISA plate with a ZIKV full-length E protein without hFc, significantly high-titer IgG antibodies were induced, particularly in the Alum and MPL-adjuvanted EDIII ( Figure 2C ), suggesting that fusion of hFc to the EDIII subunit vaccine did not affect the generation of ZIKV-specific IgG antibodies.

title:
  Effects of Adjuvants on the Immunogenicity and Efficacy of a Zika Virus Envelope Domain III Subunit Vaccine

abstract:
  Zika virus (ZIKV), a mosquito-borne flavivirus, has attracted global attention due to its close association with congenital Zika syndrome and neurological diseases, and transmission through additional routes, such as sexual contact. Currently there are no vaccines approved for ZIKV, and thus, there is an urgent need to develop an effective and safe ZIKV vaccine. Domain III (DIII) of the ZIKV envelope (E) protein is an important vaccine target, and a vaccine developed using a mutant DIII of E (EDIII) protein protects adult and pregnant mice, and unborn offspring, against ZIKV infection. Here, we have used immunocompetent BALB/c mice treated with anti-interferon-α/β receptor 1 (Ifnar1) antibodies to investigate whether three adjuvants (aluminum (Alum), monophosphoryl lipid A (MPL), and MF59), either alone or in combination, could improve the efficacy of this EDIII subunit vaccine. Our data show that, although vaccine formulated with a single adjuvant induced a specific antibody and cellular immune response, and reduced viral load in mice challenged with ZIKV, the combination of Alum and MPL adjuvants led to a more robust and balanced immune response, stronger neutralizing activity against three recent ZIKV human strains, and greater protection against a high-dose ZIKV challenge. Particularly, the combination of Alum with MPL significantly reduced viral titers and viral RNA copy numbers in sera and tissues, including the male reproductive organs. Overall, this study has identified the combination of Alum and MPL as the most effective adjuvant for ZIKV EDIII subunit vaccines, and it has important implications for subunit vaccines against other enveloped viruses, including non-ZIKV flaviviruses.


id: cord-345238-p841weif
title: The Endless Challenges of Arboviral Diseases in Brazil
author: Magalhaes, Tereza
date: 2020-05-09
txt: ./txt/cord-345238-p841weif.txt
cache: ./cache/cord-345238-p841weif.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32397512/
doi: 10.3390/tropicalmed5020075
summary:
  In this Editorial, we list and discuss some of the main challenges faced by the population and public health authorities in Brazil concerning arbovirus infections, including the occurrence of concurrent epidemics like the ongoing SARS-CoV-2/COVID-19 pandemic. Other studies suggest that the atypically low dengue incidence observed after the Zika epidemics in Brazil and other Latin American countries was due, in part, to short-term DENV protection from ZIKV infections [7, 8] . Escalating the problem of arboviral disease surveillance and management, concurrent outbreaks/epidemics of arboviruses and non-arthropod-borne pathogens can further complicate clinical diagnosis and completely overwhelm/saturate the health care system, as we may be seeing now with the pandemic of coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Lastly, concurrent epidemics like the SARS-CoV-2/COVID-19 or other respiratory pathogens/illnesses can overwhelm health care systems and further complicate clinical-epidemiological diagnoses.

abstract:
  In this Editorial, we list and discuss some of the main challenges faced by the population and public health authorities in Brazil concerning arbovirus infections, including the occurrence of concurrent epidemics like the ongoing SARS-CoV-2/COVID-19 pandemic.


id: cord-354546-lgkqwm6u
author: Yin, Yingxian
date: 2016-09-07
txt: ./txt/cord-354546-lgkqwm6u.txt
cache: ./cache/cord-354546-lgkqwm6u.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/emi.2016.100
doi: 10.1038/emi.2016.100
summary:
  7 By far, Aedes aegypti is considered the principal transmission vector of ZIKV, 8 although Aedes albopictus, which caused several outbreaks of dengue fever in Guangdong Province of South China in the last two decades, may play a role in the spread of this virus because A. These four infected individuals were first confirmed by real-time reversetranscription polymerase chain reaction (RT-PCR) in Baiyun International Airport of Guangzhou, where the youngest one (the son) had developed fever, and the family was then isolated by the local department of public health. 28 A previous study Figure 4 Phylogenetic tree based on E gene sequences of Zika virus isolates. First imported familial ZIKV cases in China Y Yin et al showed that a patient had prolonged shedding of viral RNA in saliva and urine for up to 29 days after symptom onset. In previous research, E gene sequences of ZIKV isolates were usually utilized to construct phylogenetic trees 19 based on experience from molecular study of dengue virus.

title:
  Epidemiologic investigation of a family cluster of imported ZIKV cases in Guangdong, China: probable human-to-human transmission

abstract:
  Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that can potentially threaten South China. A Chinese family of four returning from Venezuela to China was found to be positive for ZIKV when the youngest son's fever was first detected at an airport immigration inspection. They were isolated temporarily in a local hospital in Enping city, Guangdong province, where their clinical data were recorded and urine and saliva were collected to isolate ZIKV and to obtain viral sequences. All of them except the mother presented mild symptoms of rash and fever. Envelope gene sequences from the father, daughter and son were completely identical. Phylogenetic analysis demonstrated that this strain is similar to several imported strains reported in recent months, which are all clustered into a group isolated from 2015 ZIKA outbreaks in Brazil. Together with the climatic features in Venezuela, New York and Guangdong in February, it can be concluded that our subjects are imported cases from Venezuela. With the same viral sequence being shared between family members, neither direct human-to-human nor vector transmission can be ruled out in this study, but the former seems more likely. Although our subjects had mild illness, epidemiologists and public health officials should be aware of the risk of further expansion of ZIKV transmission by local competent vectors.


