SARS-CoV-2 variants evolve convergent strategies to remodel the host response
Authors listMehdi 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 VX Whelan Wilhelm Furnon Giuditta 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
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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.
Issue number 21