Murine norovirus replicase augments RIG-I-like receptors-mediated antiviral interferon response

Peifa Yu,Yang Li,Yunlong Li,Zhijiang Miao,Yining Wang,Maikel P Peppelenbosch,Qiuwei Pan

doi:10.1016/j.antiviral.2020.104877

Abstract

Noroviruses are the main causative agents for acute viral gastroenteritis worldwide. RIG-I-like receptors (RLRs) triggered interferon (IFN) activation is essential for host defense against viral infections. In turn, viruses have developed sophisticated strategies to counteract host antiviral response. This study aims to investigate how murine norovirus (MNV) replicase interacts with RLRs-mediated antiviral IFN response. Counterintuitively, we found that the MNV replicase NS7 enhances the activation of poly (I:C)-induced IFN response and the transcription of downstream interferon-stimulated genes (ISGs). Interestingly, NS7 protein augments RIG-I and MDA5-triggered antiviral IFN response, which conceivably involves direct interactions with the caspase activation and recruitment domains (CARDs) of RIG-I and MDA5. Consistently, RIG-I and MDA5 exert anti-MNV activity in human HEK293T cells with ectopic expression of viral receptor CD300lf. This effect requires the activation of JAK/STAT pathway, and is further enhanced by NS7 overexpression. These findings revealed an unconventional role of MNV NS7 as augmenting RLRs-mediated IFN response to inhibit viral replication.

Highlights

Human noroviruses (HuNV) are positive sense single-stranded RNA viruses belonging to the Caliciviridae family (Karst et al, 2014)
We found that RIG-I_CARD induced IFN-β and interferon-stimulated genes (ISGs) transcription were enhanced by NS7 (Fig. 1E and 1F)
We found RIG-I_ΔCARD did not trigger IFN activation, which was not further triggered by NS7 (Fig. 1E and 1F). These results demonstrated that murine norovirus (MNV) NS7 positively regulates RIG-I mediated IFN signaling

Summary

Introduction

Human noroviruses (HuNV) are positive sense single-stranded RNA viruses belonging to the Caliciviridae family (Karst et al, 2014). They are the major causes of epidemic nonbacterial gastroen teritis worldwide (Bok and Green, 2012; Glass et al, 2009), progress on norovirus research has been hampered by the lack of robust cell culture systems. ORF4 overlaps with ORF2, and encodes the virulence factor (VF1), which can antagonize innate immune response to MNV infection (McFadden et al, 2011; Zhu et al, 2013). NS7 is the viral RNA-dependent RNA polymerase (RdRp) (Hogbom et al, 2009; Zamyatkin et al, 2008), responsible for viral replication

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