Evasion of Type I Interferon by SARS-CoV-2

Pei-Yong Shi,Ricardo Rajsbaum,Vineet D Menachery,Hualei Wang,Xuping Xie,Xianwen Zhang,John Yun-Chung Chen,Hongjie Xia,Zengguo Cao

doi:10.1016/j.celrep.2020.108234

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication and host immune response determine coronavirus disease 2019 (COVID-19), but studies evaluating viral evasion of immune response are lacking. Here, we use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. We identify two sets of viral proteins that antagonize IFN-I signaling through blocking signal transducer and activator of transcription 1 (STAT1)/STAT2 phosphorylation or nuclear translocation. Remarkably, SARS-CoV-2 nsp1 and nsp6 suppress IFN-I signaling more efficiently than SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Thus, when treated with IFN-I, a SARS-CoV-2 replicon replicates to a higher level than chimeric replicons containing nsp1 or nsp6 from SARS-CoV or MERS-CoV. Altogether, the study provides insights on SARS-CoV-2 evasion of IFN-I response and its potential impact on viral transmission and pathogenesis.

Highlights

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, in December 2019 and has led to a global pandemic of coronavirus disease 2019 (COVID-19) (Zhou et al, 2020; Zhu et al, 2020)
The results suggest that SARS-CoV and SARS-CoV-2 use distinct antagonisms of IFN-I production and signaling to affect disease course and transmission efficiency
The results showed that nsp6 and nsp13 significantly suppressed luciferase activity when IFN-b promoter was activated by MAVS, TANK binding kinase 1 (TBK1), or inhibitor of k-B kinase ε (IKKε) (Figure 1D)

Summary

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, in December 2019 and has led to a global pandemic of coronavirus disease 2019 (COVID-19) (Zhou et al, 2020; Zhu et al, 2020). Before SARS-CoV-2, two other highly pathogenic coronaviruses emerged in the past two decades, including severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) (Assiri et al, 2013; Huang et al, 2020). SARS-CoV-2 is an enveloped b-coronavirus from the Coronaviridae family It has a positive-sense, single-stranded RNA (Figure 1A) that encodes 16 nonstructural proteins (nsp1–16), 4 structural proteins (S [spike], E [envelop], M [membrane], and N [nucleocapsid]), and 7 accessory proteins (ORF3a, ORF3b, ORF6, ORF7a, ORF7b, ORF8, and ORF10). Understanding the molecular mechanisms of the virus and its host interactions is key to comprehending COVID-19 pathogenesis and transmission as well as developing diagnosis and countermeasures against these coronaviruses

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