Zika Virus Antagonizes Type I Interferon Responses during Infection of Human Dendritic Cells.
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.
Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, United States of America.|Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, United States of America.
James R
JR
Bowen
Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, United States of America.|Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, United States of America.
Kendra M
0000-0001-9174-1506
KM
Quicke
Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, United States of America.|Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Mohan S
MS
Maddur
Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, United States of America.|Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, United States of America.
Justin T
JT
O'Neal
Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, United States of America.|Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, United States of America.
Circe E
0000-0001-9478-8967
CE
McDonald
J. Craig Venter Institute, Rockville, Maryland, United States of America.
Nadia B
NB
Fedorova
J. Craig Venter Institute, Rockville, Maryland, United States of America.
Vinita
V
Puri
J. Craig Venter Institute, Rockville, Maryland, United States of America.
Reed S
0000-0003-3272-3484
RS
Shabman
Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, United States of America.|Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Bali
B
Pulendran
Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, United States of America.|Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, United States of America.
Mehul S
MS
Suthar
D015153:Blotting, Western; D000071457:DEAD Box Protein 58 / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000821:virology*; D005434:Flow Cytometry; D006801:Humans; D057131:Immune Evasion / Q000276:immunology*; D007370:Interferon Type I / Q000276:immunology*; D016133:Polymerase Chain Reaction; D011971:Receptors, Immunologic; D000071244:Zika Virus / Q000276:immunology; D000071243:Zika Virus Infection / Q000276:immunology*
D007370:Interferon Type I; D011971:Receptors, Immunologic; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58