Activation and evasion of type I interferon responses by SARS-CoV-2
Open accessAbstract
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.
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A main evasion strategy seems to be blocking type I interferon responses at several steps, such as viral RNA recognition, nuclear translocation of inflammatory transcription factors, and STAT1/STAT2 phosphorylation.
“A predominant strategy appears to be the inhibition of the type I interferon response58–60 at multiple points, including impaired recognition of viral RNA61,62, decreased nuclear translocation of pro-inflammatory transcription factors (such as IRF3, IRF7 and STAT1)61,63 and suppression of STAT1 and STAT2 phosphorylation64,65.”
From Immunological mechanisms of vaccine-induced protection against COVID-19 in humans (2021) · cites this paper as [65]
Functional testing supported the counteracting activity of ORF3b, ORF6, NSP1, or NSP13 on type I IFN activation, with ORF6 particularly suppressing STAT1 and STAT2 phosphorylation and STAT1 nuclear translocation.
“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).”
From COVID-19 and the human innate immune system (2021) · cites this paper as Lei et al., 2020
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“, 2011), and decreases the effectiveness of host innate antiviral defences by reducing the responsiveness of infected cells to, and antagonizing the production of, type I interferons (Lei et al., 2020; Miorin et al., 2020; Xia et al., 2020).”
- Authors
- Lei, X., Dong, X., Ma, R., Wang, W., Xiao, X., Tian, Z., Wang, C., Wang, Y., Li, L., Ren, L., Guo, F., Zhao, Z., Zhou, Z., Xiang, Z., & Wang, J.
- Affiliations
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peking University (CN)
- Corresponding author
- Zhou, Zhuo
- Xiang, Zichun
- Wang, Jianwei
- ORCID
- Venue
- Nature Communications
- Published
- 2020-07-30
- Volume
- 11
- Issue
- 1
- Pages
- 3810-3810
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7392898
- OpenAlex
- W3045802278
- Cited by
- 980
- References
- 43
- Citations by year
- 2026: 34 · 2025: 61 · 2024: 122 · 2023: 136 · 2022: 266 · 2021: 312 · 2020: 49
- FWCI
- 66.91
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81930063, 31670169, 2018ZX10301401, 81971948)
- Chinese Academy of Medical Sciences (2016‐I2M‐1‐005, 2016‐I2M‐1‐014)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Keywords
- SARS-CoV-2, type I interferon, innate immune evasion, ORF6, viral nonstructural proteins, Sendai virus, viral replication inhibition, COVID-19 pathogenesis
- MeSH terms
- Betacoronavirus, COVID-19, SARS-CoV-2, Cell Line, Humans, Immunity, Innate, Interferon Type I, Mutation, Pneumonia, Viral, Promoter Regions, Genetic, Viral Proteins, Virus Replication, Signal Transduction, Open Reading Frames, Interferon-beta, Coronavirus Infections, Immune Evasion, Pandemics
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