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
2021-12-23Journal 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. (2021). 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
Emergence of SARS-CoV-2 variants of concern (VOCs) suggests viral adaptation to enhance human-to-human transmission1,2. Although much effort has focused on characterisation of spike changes in VOCs, mutations outside spike likely contribute to adaptation. Here we used unbiased abundance proteomics, phosphoproteomics, RNAseq and viral replication assays to show that isolates of the Alpha (B.1.1.7) variant3 more effectively suppress innate immune responses in airway epithelial cells, compared to first wave isolates. We found that Alpha has dramatically increased subgenomic RNA and protein levels of 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 required for RNA sensing adaptor MAVS activation. 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 Alpha transmission, and may increase in vivo replication and duration of infection4. The importance of mutations outside Spike in adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the Delta and Omicron N/Orf9b regulatory regions.
Keywords
Article, /631/326/596/4130, /631/553, /82/58, article
Sponsorship
Wellcome Trust (097997/Z/11/Z)
Wellcome Trust (097997/Z/11/A)
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/1810/334085
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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