Abstract
The pandemic of COVID-19 has posed an unprecedented threat to global public health. However, the interplay between the viral pathogen of COVID-19, SARS-CoV-2, and host innate immunity is poorly understood. Here we show that SARS-CoV-2 induces overt but delayed type-I interferon (IFN) responses. By screening 23 viral proteins, we find that SARS-CoV-2 NSP1, NSP3, NSP12, NSP13, NSP14, ORF3, ORF6 and M protein inhibit Sendai virus-induced IFN-β promoter activation, whereas NSP2 and S protein exert opposite effects. Further analyses suggest that ORF6 inhibits both type I IFN production and downstream signaling, and that the C-terminus region of ORF6 is critical for its antagonistic effect. Finally, we find that IFN-β treatment effectively blocks SARS-CoV-2 replication. In summary, our study shows that SARS-CoV-2 perturbs host innate immune response via both its structural and nonstructural proteins, and thus provides insights into the pathogenesis of SARS-CoV-2.
Highlights
IntroductionThe interplay between the viral pathogen of COVID-19, SARS-CoV-2, and host innate immunity is poorly understood
The pandemic of COVID-19 has posed an unprecedented threat to global public health
The two caspase activation recruitment domains (CARD) of retinoic acid-inducible gene I (RIG-I) and melanoma differentiation gene 5 (MDA5) could interact with the adapter mitochondrial antiviral signaling protein (MAVS, termed as IPS-1, VISA, and Cardif)[15,16,17,18], which subsequently recruits the two IKK-related kinases, TANK-binding kinase 1 (TBK1) and inducible IκB kinase (IKKi), both of which phosphorylate interferon regulatory factor 3/7 (IRF3/7)[19]
Summary
The interplay between the viral pathogen of COVID-19, SARS-CoV-2, and host innate immunity is poorly understood. We show that SARS-CoV-2 induces overt but delayed type-I interferon (IFN) responses. By screening 23 viral proteins, we find that SARS-CoV-2 NSP1, NSP3, NSP12, NSP13, NSP14, ORF3, ORF6 and M protein inhibit Sendai virus-induced IFN-β promoter activation, whereas NSP2 and S protein exert opposite effects. Our study shows that SARS-CoV-2 perturbs host innate immune response via both its structural and nonstructural proteins, and provides insights into the pathogenesis of SARS-CoV-2. PAMPs could be recognized by Toll-like receptors (TLRs), and the downstream adapter proteins TRIF or MyD88 could signal to induce cytokines and chemokines production[13,22,23]
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