Evasion of Type I Interferon by SARS-CoV-2

TLDR

SARS‑CoV‑2 replication and host immune response determine COVID‑19 severity, yet how the virus evades immunity remains poorly understood. The study seeks to identify SARS‑CoV‑2 proteins that antagonize type I interferon (IFN‑I) response. Unbiased screening was used to discover these proteins. Three proteins—nsp6, nsp13, and ORF6—block IFN‑I production by targeting TBK1 and IRF3, while additional proteins inhibit STAT1/STAT2 signaling; nsp1 and nsp6 suppress IFN‑I signaling more efficiently than SARS‑CoV and MERS‑CoV, resulting in higher replicon replication under IFN‑I treatment and underscoring the virus’s evasion tactics and potential effects on transmission and pathogenesis.

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.