Evolution of enhanced innate immune evasion by SARS-CoV-2.
Authors
Bouhaddou, Mehdi
Reuschl, Ann-Kathrin
Zuliani-Alvarez, Lorena
Pelin, Adrian
Batra, Jyoti
Whelan, Matthew VX
Ummadi, Manisha
Rojc, Ajda
Turner, Jane
Bischof, Marie L
Soucheray, Margaret
Richards, Alicia
Harjai, Bhavya
Hiatt, Joseph
Rosales, Romel
Fabius, Jacqueline M
Takeuchi, Yasu
Beltrao, Pedro
Publication Date
2022-02Journal Title
Nature
ISSN
0028-0836
Publisher
Springer Science and Business Media LLC
Volume
602
Issue
7897
Pages
487-495
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Thorne, L. G., Bouhaddou, M., Reuschl, A., Zuliani-Alvarez, L., Polacco, B., Pelin, A., Batra, J., et al. (2022). Evolution of enhanced innate immune evasion by SARS-CoV-2.. Nature, 602 (7897), 487-495. https://doi.org/10.1038/s41586-021-04352-y
Abstract
The emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission1,2. Although much effort has focused on the characterization of changes in the spike protein in variants of concern, mutations outside of spike are likely to contribute to adaptation. Here, using unbiased abundance proteomics, phosphoproteomics, RNA sequencing and viral replication assays, we show that isolates of the Alpha (B.1.1.7) variant3 suppress innate immune responses in airway epithelial cells more effectively than first-wave isolates. We found that the Alpha variant has markedly increased subgenomic RNA and protein levels of the nucleocapsid protein (N), Orf9b and Orf6-all known innate immune antagonists. Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein that is required for activation of the RNA-sensing adaptor MAVS. Moreover, the activity of Orf9b and its association with TOM70 was regulated by phosphorylation. We propose that more effective innate immune suppression, through enhanced expression of specific viral antagonist proteins, increases the likelihood of successful transmission of the Alpha variant, and may increase in vivo replication and duration of infection4. The importance of mutations outside the spike coding region in the adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the N and Orf9b regulatory regions of the Delta and Omicron variants.
Keywords
Article, /631/326/596/4130, /631/553, /82/58, article
Sponsorship
Wellcome Trust (097997/Z/11/Z)
Wellcome Trust (097997/Z/11/A)
National Institutes of Health (NIH) (via Mount Sinai School of Medicine (MSSM)) (HHSN272201400008C)
Wellcome Trust (207498/Z/17/Z)
MRC (via Imperial College London) (MR/W005611/1)
Identifiers
s41586-021-04352-y, 4352
External DOI: https://doi.org/10.1038/s41586-021-04352-y
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334229
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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