Viperin is an important host restriction factor in control of Zika virus infection

Kylie H Van Der Hoek,Nicholas S Eyre,Matthew J Gartner,Byron Shue,Michael R Beard,Lachlan A Jolly,Paul Q Thomas,Jillian M Carr,Kittirat Glab-Ampi,Claire T Roberts,Onruedee Khantisitthiporn,Fatwa Adikusuma,Tanja Jankovic-Karasoulos,Karla J Helbig

doi:10.1038/s41598-017-04138-1

Abstract

Zika virus (ZIKV) infection has emerged as a global health threat and infection of pregnant women causes intrauterine growth restriction, spontaneous abortion and microcephaly in newborns. Here we show using biologically relevant cells of neural and placental origin that following ZIKV infection, there is attenuation of the cellular innate response characterised by reduced expression of IFN-β and associated interferon stimulated genes (ISGs). One such ISG is viperin that has well documented antiviral activity against a wide range of viruses. Expression of viperin in cultured cells resulted in significant impairment of ZIKV replication, while MEFs derived from CRISPR/Cas9 derived viperin−/− mice replicated ZIKV to higher titers compared to their WT counterparts. These results suggest that ZIKV can attenuate ISG expression to avoid the cellular antiviral innate response, thus allowing the virus to replicate unchecked. Moreover, we have identified that the ISG viperin has significant anti-ZIKV activity. Further understanding of how ZIKV perturbs the ISG response and the molecular mechanisms utilised by viperin to suppress ZIKV replication will aid in our understanding of ZIKV biology, pathogenesis and possible design of novel antiviral strategies.

Highlights

Zika virus (ZIKV) is an arbovirus and a member of the Flaviviridae family that is a significant health threat on a global scale[1]
Huh-7 cells were readily infected by ZIKV resulting in spreading infection that resulted in significant cytopathic effect (CPE) at 72 hr post-infection (h.p.i)[30]
We previously reported that infection of Huh-7 cells with the closely related flavivirus dengue virus (DENV) results in significant interferon stimulated genes (ISGs) expression; this was not the case with ZIKV infection[24]

Summary

Introduction

Zika virus (ZIKV) is an arbovirus and a member of the Flaviviridae family that is a significant health threat on a global scale[1]. This, together with the observations that placental cells can resist ZIKV infection due to the actions of the type III IFN-λ and susceptibility of Ifnar−/− mice to ZIKV infection suggests a role for specific ISGs in control of ZIKV infection[21] With this in mind we investigated the innate response to ZIKV infection and revealed that ZIKV infected cells of neural and placental origin fail to induce a robust ISG response. We and others have demonstrated that the evolutionary conserved ISG viperin can inhibit the replication of a wide range of viruses that are responsible for significant disease in humans[23] These include the Flaviviridae family members, DENV, TBEV, WNV and HCV24–28. Understanding the ISGs that control ZIKV and other emerging viral infections is essential for defining mechanisms of viral pathogenesis and possible novel therapeutic strategies

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