Abstract
SARS-CoV-2 is the pathogenic agent of COVID-19, which has evolved into a global pandemic. Compared with some other respiratory RNA viruses, SARS-CoV-2 is a poor inducer of type I interferon (IFN). Here, we report that SARS-CoV-2 nsp12, the viral RNA-dependent RNA polymerase (RdRp), suppresses host antiviral responses. SARS-CoV-2 nsp12 attenuated Sendai virus (SeV)- or poly(I:C)-induced IFN-β promoter activation in a dose-dependent manner. It also inhibited IFN promoter activation triggered by RIG-I, MDA5, MAVS, and IRF3 overexpression. Nsp12 did not impair IRF3 phosphorylation but suppressed the nuclear translocation of IRF3. Mutational analyses suggested that this suppression was not dependent on the polymerase activity of nsp12. Given these findings, our study reveals that SARS-CoV-2 RdRp can antagonize host antiviral innate immunity and thus provides insights into viral pathogenesis.
Highlights
Coronavirus disease 2019 (COVID-19) has evolved into a global pandemic
SARS-CoV-2 nsp[12] attenuates type I IFN activation To examine whether SARS-CoV-2 nsp[12] could regulate innate immune responses, we first evaluated the effect of nsp[12] on IFN-β promoter activation. 293T cells were transiently transfected with a vector plasmid or plasmids expressing nsp[12] along with an IFN-β promoter-driven luciferase reporter plasmid and a control pRL-TK plasmid
We further investigated whether nsp[12] affects signaling pathways downstream of IFN-β production. 293T cells were transiently transfected with a vector plasmid or with plasmids expressing nsp[12] along with an interferon-stimulated response element (ISRE) reporter plasmid and a control pRL-TK plasmid
Summary
Coronavirus disease 2019 (COVID-19) has evolved into a global pandemic. According to the WHO Coronavirus Disease dashboard, there were 63,360,234 confirmed cases of COVID-19, including 1,475,825 deaths, as of 2 December 2020 (https://covid19.who.int/).Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as the pathogenic agent of COVID-19.1–3 The International Committee on Taxonomy of Viruses has classified SARS-CoV-2 into the Coronaviridae family, the Orthocoronavirinae subfamily, the Betacoronaviruses genus, and the Sarbecovirus subgenus.[4]SARS-CoV-2 is a positive-stranded RNA virus with a genome of ~29.7 kb.[1]. Coronavirus disease 2019 (COVID-19) has evolved into a global pandemic. According to the WHO Coronavirus Disease dashboard, there were 63,360,234 confirmed cases of COVID-19, including 1,475,825 deaths, as of 2 December 2020 (https://covid19.who.int/). Two large replicase polyproteins (pp1a and pp1ab) are first synthesized. They are cleaved into 16 nonstructural proteins (nsps), including nsp[12], a viral RNA-dependent RNA polymerase (RdRp), by papain-like protease (nsp3) and 3C-like protease (nsp5).[5] Viral nsps leverage the host cell membrane structure to assemble into replication and transcription complexes that engage in minus-strand RNA synthesis.[5,6] Subgenomic RNAs are synthesized, and the structural and accessory proteins are expressed
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