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

Bouhaddou, Mehdi; Reuschl, Ann-Kathrin; Polacco, Benjamin J; Thorne, Lucy G; Ummadi, Manisha R; Ye, Chengjin; Rosales, Romel; ... Krogan, Nevan J; + view all (2023) SARS-CoV-2 variants evolve convergent strategies to remodel the host response. Cell 10.1016/j.cell.2023.08.026. (In press).

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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.

Type: Article
Title: SARS-CoV-2 variants evolve convergent strategies to remodel the host response
Location: United States
DOI: 10.1016/j.cell.2023.08.026
Publisher version: https://doi.org/10.1016/j.cell.2023.08.026
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: innate immunity, protein-protein interactions, proteomics, SARS-CoV-2, systems biology, transcriptomics, variants, virus-host interactions
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/10178258
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