SARS-CoV-2 ORF3b Is a Potent Interferon Antagonist Whose Activity Is Increased by a Naturally Occurring Elongation Variant
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Abstract
Abstract One of the features distinguishing SARS-CoV-2 from its more pathogenic counterpart SARS-CoV is the presence of premature stop codons in its ORF3b gene. Here, we show that SARS-CoV-2 ORF3b is a potent interferon antagonist, suppressing the induction of type I interferon more efficiently than its SARS-CoV ortholog. Phylogenetic analyses and functional assays revealed that SARS-CoV-2-related viruses from bats and pangolins also encode truncated ORF3b gene products with strong anti-interferon activity. Furthermore, analyses of more than 15,000 SARS-CoV-2 sequences identified a natural variant, in which a longer ORF3b reading frame was reconstituted. This variant was isolated from two patients with severe disease and further increased the ability of ORF3b to suppress interferon induction. Thus, our findings not only help to explain the poor interferon response in COVID-19 patients, but also describe a possibility of the emergence of natural SARS-CoV-2 quasispecies with extended ORF3b that may exacerbate COVID-19 symptoms. Highlights ORF3b of SARS-CoV-2 and related bat and pangolin viruses is a potent IFN antagonist SARS-CoV-2 ORF3b suppresses IFN induction more efficiently than SARS-CoV ortholog The anti-IFN activity of ORF3b depends on the length of its C-terminus An ORF3b with increased IFN antagonism was isolated from two severe COVID-19 cases
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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 [64]
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 Konno et al., 2020
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- Authors
- Konno, Y., Kimura, I., Uriu, K., Fukushi, M., Irie, T., Koyanagi, Y., Sauter, D., Gifford, R. J., Nakagawa, S., & Sato, K.
- Affiliations
- Institute of Medical Science, The University of Tokyo (JP)
- Hiroshima University (JP)
- Kyoto University (JP)
- Universität Ulm (DE)
- MRC University of Glasgow Centre for Virus Research (GB)
- Tokai University (JP)
- Corresponding author
- Sato, Kei
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 32
- Issue
- 12
- Pages
- 108185
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC7473339
- OpenAlex
- W3082709602
- Cited by
- 433
- References
- 48
- Citations by year
- 2026: 7 · 2025: 23 · 2024: 35 · 2023: 48 · 2022: 101 · 2021: 155 · 2020: 64
- FWCI
- 12.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Takeda Science Foundation
- Daiichi Sankyo Foundation of Life Science
- Bundesministerium für Bildung und Forschung
- Japan Agency for Medical Research and Development (20fk0410014, 20fk0108146, 19fk0108171, 20fk0108270, 19fk0410019)
- Uehara Memorial Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Institute of Medical Science, University of Tokyo
- Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg
- Canon Foundation in Europe
- Lotte Foundation
- Institute for Frontier Life and Medical Sciences, Kyoto University
- Ono Medical Research Foundation
- University of Tokyo (2020-K3003)
- Japan Society for the Promotion of Science (17H05823, 19H04843, 19H04837, 17H05813, 19H04826, 18H02662, 16K21723, 16H06429, DC1 19J22914, DC1 19J20488)
- Hiroshima University
- Sumitomo Foundation
- Japan Science and Technology Agency (JPMJJR2007)
- Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Keywords
- SARS-CoV-2, interferon antagonism, type I interferon induction, premature stop codon, SARS-CoV, bat coronaviruses, pangolin coronavirus, quasispecies, COVID-19 pathogenesis, severe COVID-19
- MeSH terms
- Eutheria, Betacoronavirus, COVID-19, SARS-CoV-2, Adult, Amino Acid Sequence, Animals, Chiroptera, Humans, Interferon Type I, Male, Pneumonia, Viral, Coronavirus Infections, Codon, Nonsense, Viral Regulatory and Accessory Proteins, Pandemics
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