SARS-CoV-2 variants evolve convergent strategies to remodel the host response

Mehdi Bouhaddou, Ann Kathrin Reuschl, Benjamin J. Polacco, Lucy G. Thorne, Manisha R. Ummadi, Chengjin Ye, Romel Rosales, Adrian Pelin, Jyoti Batra, Gwendolyn M. Jang, Jiewei Xu, Jack M. Moen, Alicia L. Richards, Yuan Zhou, Bhavya Harjai, Erica Stevenson, Ajda Rojc, Roberta Ragazzini, Matthew V.X. Whelan, Wilhelm FurnonGiuditta De Lorenzo, Vanessa Cowton, Abdullah M. Syed, Alison Ciling, Noa Deutsch, Daniel Pirak, Giulia Dowgier, Dejan Mesner, Jane L. Turner, Briana L. McGovern, M. Luis Rodriguez, Rocio Leiva-Rebollo, Alistair S. Dunham, Xiaofang Zhong, Manon Eckhardt, Andrea Fossati, Nicholas F. Liotta, Thomas Kehrer, Anastasija Cupic, Magdalena Rutkowska, Ignacio Mena, Sadaf Aslam, Alyssa Hoffert, Helene Foussard, Charles Ochieng’ Olwal, Weiqing Huang, Thomas Zwaka, John Pham, Molly Lyons, Laura Donohue, Aliesha Griffin, Rebecca Nugent, Kevin Holden, Robert Deans, Pablo Aviles, Jose A. Lopez-Martin, Jose M. Jimeno, Kirsten Obernier, Jacqueline M. Fabius, Margaret Soucheray, Ruth Hüttenhain, Irwin Jungreis, Manolis Kellis, Ignacia Echeverria, Kliment Verba, Paola Bonfanti, Pedro Beltrao, Roded Sharan, Jennifer A. Doudna, Luis Martinez-Sobrido, Arvind H. Patel, Massimo Palmarini, Lisa Miorin, Kris White, Danielle L. Swaney, Adolfo Garcia-Sastre*, Clare Jolly*, Lorena Zuliani-Alvarez*, Greg J. Towers*, Nevan J. Krogan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

SARS-CoV-2 variants of concern (VOCs) emerged during the COVID-19 pandemic. Here, we used unbiased systems approaches to study the host-selective forces driving VOC evolution. We discovered that VOCs evolved convergent strategies to remodel the host by modulating viral RNA and protein levels, altering viral and host protein phosphorylation, and rewiring virus-host protein-protein interactions. Integrative computational analyses revealed that although Alpha, Beta, Gamma, and Delta ultimately converged to suppress interferon-stimulated genes (ISGs), Omicron BA.1 did not. ISG suppression correlated with the expression of viral innate immune antagonist proteins, including Orf6, N, and Orf9b, which we mapped to specific mutations. Later Omicron subvariants BA.4 and BA.5 more potently suppressed innate immunity than early subvariant BA.1, which correlated with Orf6 levels, although muted in BA.4 by a mutation that disrupts the Orf6-nuclear pore interaction. Our findings suggest that SARS-CoV-2 convergent evolution overcame human adaptive and innate immune barriers, laying the groundwork to tackle future pandemics.

Original languageEnglish
Pages (from-to)4597-4614.e26
JournalCell
Volume186
Issue number21
DOIs
StatePublished - 12 Oct 2023

Funding

FundersFunder number
CRIPT
N-fold LLC
National Institutes of HealthU19AI135990, U19AI171110, U19AI135972, 133122P
National Institute of Allergy and Infectious Diseases75N93021C00014
Pfizer
Merck
F. Hoffmann-La Roche
Vir Biotechnology
Senhwa Biosciences

    Keywords

    • SARS-CoV-2
    • innate immunity
    • protein-protein interactions
    • proteomics
    • systems biology
    • transcriptomics
    • variants
    • virus-host interactions

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