Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant
By
Lucy G Thorne,
Mehdi Bouhaddou,
Ann-Kathrin Reuschl,
Lorena Zuliani-Alvarez,
Benjamin J. Polacco,
Adrian Pelin,
Jyoti Batra,
Matthew VX Whelan,
Manisha Ummadi,
Ajda Roic,
Jane Turner,
Kirsten Obernier,
Hannes Braberg,
Margaret Soucheray,
Alicia L. Richards,
Kuei-Ho Chen,
Bhavya Harjai,
Danish Memon,
Myra Hosmillo,
Joseph Hiatt,
Aminu S. Jahun,
Ian G. Goodfellow,
Mahdad Noursadeghi,
Jacqueline Fabius,
Kevan M Shokat,
Natalia Jura,
Kliment A Verba,
Pedro Beltrao,
Danielle L Swaney,
Adolfo GarcĂa-Sastre,
Clare Jolly,
Greg J. Towers,
Nevan J Krogan
Posted 07 Jun 2021
bioRxiv DOI: 10.1101/2021.06.06.446826
Emergence of SARS-CoV-2 variants, including the globally successful B.1.1.7 lineage, suggests viral adaptations to host selective pressures resulting in more efficient transmission. Although much effort has focused on Spike adaptation for viral entry and adaptive immune escape, B.1.1.7 mutations outside Spike likely contribute to enhance transmission. Here we used unbiased abundance proteomics, phosphoproteomics, mRNA sequencing and viral replication assays to show that B.1.1.7 isolates more effectively suppress host innate immune responses in airway epithelial cells. We found that B.1.1.7 isolates have dramatically increased subgenomic RNA and protein levels of Orf9b and Orf6, both 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, and Orf9b binding and activity was regulated via phosphorylation. We conclude that B.1.1.7 has evolved beyond the Spike coding region to more effectively antagonise host innate immune responses through upregulation of specific subgenomic RNA synthesis and increased protein expression of key innate immune antagonists. We propose that more effective innate immune antagonism increases the likelihood of successful B.1.1.7 transmission, and may increase in vivo replication and duration of infection.
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