Evolution of enhanced innate immune evasion by SARS-CoV-2

Lucy G. Thorne, Mehdi Bouhaddou, Ann-Kathrin Reuschl, Lorena Zuliani-Alvarez, Ben Polacco, Adrian Pelin, Jyoti Batra, Matthew V. X. Whelan, Myra Hosmillo, Andrea Fossati, Roberta Ragazzini, Irwin Jungreis, Manisha Ummadi, Ajda Rojc, Jane Turner, Marie L. Bischof, Kirsten Obernier, Hannes Braberg, Margaret Soucheray, Alicia Richards, Kuei-Ho Chen, Bhavya Harjai, Danish Memon, Joseph Hiatt, Romel Rosales, Briana L. McGovern, Aminu Jahun, Jacqueline M. Fabius, Kris White, Ian G. Goodfellow, Yasu Takeuchi, Paola Bonfanti, Kevan Shokat, Natalia Jura, Klim Verba, Mahdad Noursadeghi, Pedro Beltrao, Manolis Kellis, Danielle L. Swaney, Adolfo García-Sastre, Clare Jolly (), Greg J. Towers () and Nevan J. Krogan ()
Additional contact information
Lucy G. Thorne: University College London
Mehdi Bouhaddou: University of California San Francisco
Ann-Kathrin Reuschl: University College London
Lorena Zuliani-Alvarez: University of California San Francisco
Ben Polacco: University of California San Francisco
Adrian Pelin: University of California San Francisco
Jyoti Batra: University of California San Francisco
Matthew V. X. Whelan: University College London
Myra Hosmillo: Addenbrooke’s Hospital, University of Cambridge
Andrea Fossati: University of California San Francisco
Roberta Ragazzini: The Francis Crick Institute
Irwin Jungreis: MIT
Manisha Ummadi: University of California San Francisco
Ajda Rojc: University of California San Francisco
Jane Turner: University College London
Marie L. Bischof: University College London
Kirsten Obernier: University of California San Francisco
Hannes Braberg: University of California San Francisco
Margaret Soucheray: University of California San Francisco
Alicia Richards: University of California San Francisco
Kuei-Ho Chen: University of California San Francisco
Bhavya Harjai: University of California San Francisco
Danish Memon: European Bioinformatics Institute, Wellcome Genome Campus
Joseph Hiatt: University of California San Francisco
Romel Rosales: Icahn School of Medicine at Mount Sinai
Briana L. McGovern: Icahn School of Medicine at Mount Sinai
Aminu Jahun: Addenbrooke’s Hospital, University of Cambridge
Jacqueline M. Fabius: University of California San Francisco
Kris White: Icahn School of Medicine at Mount Sinai
Ian G. Goodfellow: Addenbrooke’s Hospital, University of Cambridge
Yasu Takeuchi: University College London
Paola Bonfanti: The Francis Crick Institute
Kevan Shokat: University of California San Francisco
Natalia Jura: University of California San Francisco
Klim Verba: University of California San Francisco
Mahdad Noursadeghi: University College London
Pedro Beltrao: University of California San Francisco
Manolis Kellis: MIT
Danielle L. Swaney: University of California San Francisco
Adolfo García-Sastre: Icahn School of Medicine at Mount Sinai
Clare Jolly: University College London
Greg J. Towers: University College London
Nevan J. Krogan: University of California San Francisco

Nature, 2022, vol. 602, issue 7897, 487-495

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-021-04352-y

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