PMID- 28152048 OWN - NLM STAT- MEDLINE DCOM- 20170803 LR - 20240327 IS - 1553-7374 (Electronic) IS - 1553-7366 (Print) IS - 1553-7366 (Linking) VI - 13 IP - 2 DP - 2017 Feb TI - Zika Virus Antagonizes Type I Interferon Responses during Infection of Human Dendritic Cells. PG - e1006164 LID - 10.1371/journal.ppat.1006164 [doi] LID - e1006164 AB - Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that is causally linked to severe neonatal birth defects, including microcephaly, and is associated with Guillain-Barre syndrome in adults. Dendritic cells (DCs) are an important cell type during infection by multiple mosquito-borne flaviviruses, including dengue virus, West Nile virus, Japanese encephalitis virus, and yellow fever virus. Despite this, the interplay between ZIKV and DCs remains poorly defined. Here, we found human DCs supported productive infection by a contemporary Puerto Rican isolate with considerable variability in viral replication, but not viral binding, between DCs from different donors. Historic isolates from Africa and Asia also infected DCs with distinct viral replication kinetics between strains. African lineage viruses displayed more rapid replication kinetics and infection magnitude as compared to Asian lineage viruses, and uniquely induced cell death. Infection of DCs with both contemporary and historic ZIKV isolates led to minimal up-regulation of T cell co-stimulatory and MHC molecules, along with limited secretion of inflammatory cytokines. Inhibition of type I interferon (IFN) protein translation was observed during ZIKV infection, despite strong induction at the RNA transcript level and up-regulation of other host antiviral proteins. Treatment of human DCs with RIG-I agonist potently restricted ZIKV replication, while type I IFN had only modest effects. Mechanistically, we found all strains of ZIKV antagonized type I IFN-mediated phosphorylation of STAT1 and STAT2. Combined, our findings show that ZIKV subverts DC immunogenicity during infection, in part through evasion of type I IFN responses, but that the RLR signaling pathway is still capable of inducing an antiviral state, and therefore may serve as an antiviral therapeutic target. FAU - Bowen, James R AU - Bowen JR AD - Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, United States of America. AD - Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, United States of America. FAU - Quicke, Kendra M AU - Quicke KM AUID- ORCID: 0000-0001-9174-1506 AD - Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, United States of America. AD - Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, United States of America. FAU - Maddur, Mohan S AU - Maddur MS AD - Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, United States of America. AD - Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America. FAU - O'Neal, Justin T AU - O'Neal JT AD - Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, United States of America. AD - Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, United States of America. FAU - McDonald, Circe E AU - McDonald CE AUID- ORCID: 0000-0001-9478-8967 AD - Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, United States of America. AD - Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, United States of America. FAU - Fedorova, Nadia B AU - Fedorova NB AD - J. Craig Venter Institute, Rockville, Maryland, United States of America. FAU - Puri, Vinita AU - Puri V AD - J. Craig Venter Institute, Rockville, Maryland, United States of America. FAU - Shabman, Reed S AU - Shabman RS AUID- ORCID: 0000-0003-3272-3484 AD - J. Craig Venter Institute, Rockville, Maryland, United States of America. FAU - Pulendran, Bali AU - Pulendran B AD - Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, United States of America. AD - Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America. FAU - Suthar, Mehul S AU - Suthar MS AD - Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, United States of America. AD - Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, United States of America. LA - eng GR - R37 AI048638/AI/NIAID NIH HHS/United States GR - R38 AI140299/AI/NIAID NIH HHS/United States GR - U19 AI057266/AI/NIAID NIH HHS/United States GR - R37 DK057665/DK/NIDDK NIH HHS/United States GR - U19 AI110819/AI/NIAID NIH HHS/United States GR - U19 AI090023/AI/NIAID NIH HHS/United States GR - U19 AI083019/AI/NIAID NIH HHS/United States GR - R56 AI110516/AI/NIAID NIH HHS/United States GR - P51 OD011132/OD/NIH HHS/United States GR - R21 AI113485/AI/NIAID NIH HHS/United States PT - Journal Article DEP - 20170202 PL - United States TA - PLoS Pathog JT - PLoS pathogens JID - 101238921 RN - 0 (Interferon Type I) RN - 0 (Receptors, Immunologic) RN - EC 3.6.1.- (RIGI protein, human) RN - EC 3.6.4.13 (DEAD Box Protein 58) SB - IM MH - Blotting, Western MH - DEAD Box Protein 58/*immunology MH - Dendritic Cells/immunology/*virology MH - Flow Cytometry MH - Humans MH - Immune Evasion/*immunology MH - Interferon Type I/*immunology MH - Polymerase Chain Reaction MH - Receptors, Immunologic MH - Zika Virus/immunology MH - Zika Virus Infection/*immunology PMC - PMC5289613 COIS- The authors have declared that no competing interests exist. EDAT- 2017/02/06 06:00 MHDA- 2017/08/05 06:00 PMCR- 2017/02/02 CRDT- 2017/02/03 06:00 PHST- 2016/09/01 00:00 [received] PHST- 2017/01/02 00:00 [accepted] PHST- 2017/02/03 06:00 [entrez] PHST- 2017/02/06 06:00 [pubmed] PHST- 2017/08/05 06:00 [medline] PHST- 2017/02/02 00:00 [pmc-release] AID - PPATHOGENS-D-16-02024 [pii] AID - 10.1371/journal.ppat.1006164 [doi] PST - epublish SO - PLoS Pathog. 2017 Feb 2;13(2):e1006164. doi: 10.1371/journal.ppat.1006164. eCollection 2017 Feb.