Activation and evasion of type I interferon responses by SARS-CoV-2

By X. Lei, Xiaojing Dong, Ruiyi Ma, Wenjing Wang, Xia Xiao, Zhongqin Tian, Conghui Wang, Ying Wang, Li Li, L. Ren and 5 more. 2020

899 citations recorded by the source corpus.

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. The pandemic of SARS-CoV-2 post a significant threat to public health. Here the authors show, by screening 23 viral proteins, that both structural and non-structural SARS-CoV-2 proteins are capable of modulating host innate immunity and type interferon responses, with this information serves to warrant further studies on SARS-CoV-2 pathogenesis.

Subfields: Immunology, Infectious Diseases

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Citations in the corpus

COVID-19 and the human innate immune system (2021, background): “Functional testing further supported the counteracting activity of ORF3b, ORF6, NSP1, or NSP13 on type I IFN activation, of which particularly ORF6 suppressed STAT1 and STAT2 phosphorylation and STAT1 nuclear translocation, (Konno et al., 2020; Lei et al., 2020; Xia et al., 2020).”
Host cell-intrinsic innate immune recognition of SARS-CoV-2 (2021, positive): “Host translation shut-off The Nsp1 protein is a potent IFN antagonist that blocks IFN induction and signaling [71 ,72,73].”
SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling (2020, background): “global analysis of SARS-CoV-2 host interacting proteins recently identified the Nup98-Rae1 complex as a high-confidence SARSCoV-2 Orf6 binding partner (39).”
Mechanisms of SARS-CoV-2 Transmission and Pathogenesis (2020, positive): “This potent suppressive function of nsp1 also appears to bemaintained in SARS-CoV-2, primarily through shutdown of translational machinery and prevention of immune gene expression [101,104,105].”
Sarbecovirus ORF6 proteins hamper induction of interferon signaling (2021, positive): “Additionally, all previous studies characterizing the anti-innate immuneactivity ofORF6 (Lei et al., 2020; Li et al., 2020a;Miorin et al., 2020; Xia et al., 2020; Yuen et al., 2020) have exclusively used overexpression systems, mainly in HEK293 cells.”
Evasion of Type I Interferon by SARS-CoV-2 (2020, positive): “SARS-CoV-2 infection induces a delayed IFN-I response (Lei et al., 2020).”
Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant (2021, background): “Orf6 is known to antagonise the innate response through inhibition of transcription factor STAT1 and IRF3 nuclear entry 13,24 .”