STAT5: a Target of Antagonism by Neurotropic Flaviviruses.

Autor:	Zimmerman MG; Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA.; Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, USA., Bowen JR; Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA.; Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, USA., McDonald CE; Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA.; Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, USA., Young E; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA., Baric RS; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA.; Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA., Pulendran B; Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, USA.; Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA., Suthar MS; Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA msuthar@emory.edu.; Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, USA.
Jazyk:	angličtina
Zdroj:	Journal of virology [J Virol] 2019 Nov 13; Vol. 93 (23). Date of Electronic Publication: 2019 Nov 13 (Print Publication: 2019).
DOI:	10.1128/JVI.00665-19
Abstrakt:	Flaviviruses are a diverse group of arthropod-borne viruses responsible for numerous significant public health threats; therefore, understanding the interactions between these viruses and the human immune response remains vital. West Nile virus (WNV) and Zika virus (ZIKV) infect human dendritic cells (DCs) and can block antiviral immune responses in DCs. Previously, we used mRNA sequencing and weighted gene coexpression network analysis (WGCNA) to define molecular signatures of antiviral DC responses following activation of innate immune signaling (RIG-I, MDA5, or type I interferon [IFN] signaling) or infection with WNV. Using this approach, we found that several genes involved in T cell cosignaling and antigen processing were not enriched in DCs during WNV infection. Using cis -regulatory sequence analysis, STAT5 was identified as a regulator of DC activation and immune responses downstream of innate immune signaling that was not activated during either WNV or ZIKV infection. Mechanistically, WNV and ZIKV actively blocked STAT5 phosphorylation downstream of RIG-I, IFN-β, and interleukin-4 (IL-4), but not granulocyte-macrophage colony-stimulating factor (GM-CSF), signaling. Unexpectedly, dengue virus serotypes 1 to 4 (DENV1 to DENV4) and the yellow fever 17D vaccine strain (YFV-17D) did not antagonize STAT5 phosphorylation. In contrast to WNV, ZIKV inhibited JAK1 and TYK2 phosphorylation following type I IFN treatment, suggesting divergent mechanisms used by these viruses to inhibit STAT5 activation. Combined, these findings identify STAT5 as a target of antagonism by specific pathogenic flaviviruses to subvert the immune response in infected DCs. IMPORTANCE Flaviviruses are a diverse group of insect-borne viruses responsible for numerous significant public health threats. Previously, we used a computational biology approach to define molecular signatures of antiviral DC responses following activation of innate immune signaling or infection with West Nile virus (WNV). In this work, we identify STAT5 as a regulator of DC activation and antiviral immune responses downstream of innate immune signaling that was not activated during either WNV or Zika virus (ZIKV) infection. WNV and ZIKV actively blocked STAT5 phosphorylation downstream of RIG-I, IFN-β, and IL-4, but not GM-CSF, signaling. However, other related flaviviruses, dengue virus serotypes 1 to 4 and the yellow fever 17D vaccine strain, did not antagonize STAT5 phosphorylation. Mechanistically, WNV and ZIKV showed differential inhibition of Jak kinases upstream of STAT5, suggesting divergent countermeasures to inhibit STAT5 activation. Combined, these findings identify STAT5 as a target of antagonism by specific pathogenic flaviviruses to subvert antiviral immune responses in human DCs. (Copyright © 2019 American Society for Microbiology.)
Databáze:	MEDLINE
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