Evasion of Type I Interferon by SARS-CoV-2

By Hongjie Xia, Zengguo Cao, Xuping Xie, Xianwen Zhang, J. Chen, Hualei Wang, Vineet D. Menachery, Ricardo Rajsbaum, P. Shi. Cell Reports, 2020

864 citations recorded by the source corpus.

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.

Subfields: Immunology, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/054c380f71f57f855d2cc13b84bdbae9782ad4d3

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. A. García‐Sastre
2. A. Aschenbrenner
3. Andrew G. Harrison
4. Tao Lin
5. Joachim L. Schultze
6. Penghua Wang

In Infectious Diseases

1. A. Aschenbrenner
2. Andrew G. Harrison
3. Tao Lin
4. Joachim L. Schultze
5. Penghua Wang

Citations in the corpus

• COVID-19 and the human innate immune system (2021, background): “Interaction mapping further suggested that NSP13 interacts with TBK1, NSP15 with NRDP1 (an E3 ubiquitin ligase controlling the balance between JAK2-associated cytokine receptor degradation and ectodomain shedding), ORF9b with TOMM70 (an important receptor of the outer mitochondrial membrane), and OR”
• Mechanisms of SARS-CoV-2 Transmission and Pathogenesis (2020, positive): “Coincidently, the apparent loss of these proteins may provide evidence for why MERS-CoV is more sensitive to IFN treatment than are SARS-CoVs in primary and continuous cells of the human airways [110].”
• Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant (2021, background): “However, given SARS-CoV-2 encodes multiple, functionally overlapping innate immune antagonists 12–14 , it is possible that B.1.1.7 protein variation, for example in Nsp3 or Nsp6, could also contribute to enhanced immune antagonism.”
• 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).”
• Sarbecovirus ORF6 proteins hamper induction of interferon signaling (2021, neutral): “During the review process of this paper, several recent publications have described mechanisms of IFN-I antagonism by different SARS-CoV-2 proteins, including ORF6 (Lei et al., 2020; Li et al., 2020a; Miorin et al., 2020; Xia et al., 2020; Yuen et al., 2020).”