Infection with a Brazilian isolate of Zika virus generates RIG-I stimulatory RNA and the viral NS5 protein blocks type I IFN induction and signaling.

Jonny Hertzog,Philip Hublitz,Claire L Donald,Rachel E Rigby,Christian Eggeling,Erdinc Sezgin,Chaojun Song,Jan Rehwinkel,Alain Kohl,Alice Mayer,Antonio Gregorio Dias Junior,Boquan Jin

doi:10.1002/eji.201847483

Abstract

Zika virus (ZIKV) is a major public health concern in the Americas. We report that ZIKV infection and RNA extracted from ZIKV infected cells potently activated the induction of type I interferons (IFNs). This effect was fully dependent on the mitochondrial antiviral signaling protein (MAVS), implicating RIG‐I‐like receptors (RLRs) as upstream sensors of viral RNA. Indeed, RIG‐I and the related RNA sensor MDA5 contributed to type I IFN induction in response to RNA from infected cells. We found that ZIKV NS5 from a recent Brazilian isolate blocked type I IFN induction downstream of RLRs and also inhibited type I IFN receptor (IFNAR) signaling. We defined the ZIKV NS5 nuclear localization signal and report that NS5 nuclear localization was not required for inhibition of signaling downstream of IFNAR. Mechanistically, NS5 blocked IFNAR signaling by both leading to reduced levels of STAT2 and by blocking phosphorylation of STAT1, two transcription factors activated by type I IFNs. Taken together, our observations suggest that ZIKV infection induces a type I IFN response via RLRs and that ZIKV interferes with this response by blocking signaling downstream of RLRs and IFNAR.

Highlights

Viruses from the Flaviviridae family are enveloped and contain a positive sense, single stranded RNA genome
Using RT-qPCR, we found that IFNβ mRNA and several transcripts encoded by interferon-stimulated genes (ISGs) were upregulated in Zika virus (ZIKV)-infected A549 cells (Fig. 1A)
It is important to understand how such responses are initiated and how viruses evade and antagonize them. We studied this question in the context of the emerging pathogen ZIKV, and show that ZIKV infection generates RNA molecules that stimulate RIG-I and MDA5

Summary

Introduction

Viruses from the Flaviviridae family are enveloped and contain a positive sense, single stranded RNA genome. The 2015/2016 epidemic strain belongs to the Asian lineage and shares a common ancestor with viruses causing outbreaks in Polynesia in 2013/2014 [3, 4]. ZIKV is most commonly transmitted by Aedes mosquitoes; other routes of transmission include sexual and maternal-fetal during pregnancy [8,9,10]. In the latter case, in utero ZIKV infection may cause developmental defects resulting in microcephaly [11]. ZIKV infects neural progenitor cells and vertical transmission as well as fetal microcephaly have been documented in mouse models [reviewed in: [7]]

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Conclusion