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 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

doi:10.1016/j.cell.2023.08.026

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

Cell. 2023 Oct 12;186(21):4597-4614.e26. doi: 10.1016/j.cell.2023.08.026. Epub 2023 Sep 21.

Authors

Mehdi Bouhaddou¹, Ann-Kathrin Reuschl², Benjamin J Polacco³, Lucy G Thorne², Manisha R Ummadi³, Chengjin Ye⁴, Romel Rosales⁵, Adrian Pelin³, Jyoti Batra³, Gwendolyn M Jang³, Jiewei Xu³, Jack M Moen³, Alicia L Richards³, Yuan Zhou³, Bhavya Harjai³, Erica Stevenson³, Ajda Rojc³, Roberta Ragazzini⁶, Matthew V X Whelan⁷, Wilhelm Furnon⁸, Giuditta De Lorenzo⁸, Vanessa Cowton⁸, Abdullah M Syed⁹, Alison Ciling⁹, Noa Deutsch¹⁰, Daniel Pirak¹¹, Giulia Dowgier¹², Dejan Mesner⁷, Jane L Turner⁷, Briana L McGovern¹³, M Luis Rodriguez¹³, Rocio Leiva-Rebollo⁵, Alistair S Dunham¹⁴, Xiaofang Zhong³, Manon Eckhardt³, Andrea Fossati³, Nicholas F Liotta¹⁵, Thomas Kehrer¹⁶, Anastasija Cupic¹⁶, Magdalena Rutkowska¹⁶, Ignacio Mena⁵, Sadaf Aslam⁵, Alyssa Hoffert³, Helene Foussard³, Charles Ochieng' Olwal¹⁷, Weiqing Huang¹⁸, Thomas Zwaka¹⁸, John Pham¹⁹, Molly Lyons¹⁹, Laura Donohue¹⁹, Aliesha Griffin¹⁹, Rebecca Nugent¹⁹, Kevin Holden¹⁹, Robert Deans¹⁹, Pablo Aviles²⁰, Jose A Lopez-Martin²⁰, Jose M Jimeno²⁰, Kirsten Obernier³, Jacqueline M Fabius³, Margaret Soucheray³, Ruth Hüttenhain³, Irwin Jungreis²¹, Manolis Kellis²¹, Ignacia Echeverria²², Kliment Verba²², Paola Bonfanti⁶, Pedro Beltrao²³, Roded Sharan¹⁰, Jennifer A Doudna²⁴, Luis Martinez-Sobrido⁴, Arvind H Patel⁸, Massimo Palmarini⁸, Lisa Miorin⁵, Kris White⁵, Danielle L Swaney³, Adolfo Garcia-Sastre²⁵, Clare Jolly²⁶, Lorena Zuliani-Alvarez²⁷, Greg J Towers²⁸, Nevan J Krogan²⁹

Affiliations

¹ Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA; QBI Coronavirus Research Group (QCRG), University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology, Immunology, and Molecular Genetics (MIMG), University of California, Los Angeles, Los Angeles, CA, USA; Institute for Quantitative and Computational Biosciences (QCBio), University of California, Los Angeles, Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
² QBI Coronavirus Research Group (QCRG), University of California, San Francisco, San Francisco, CA, USA; Division of Infection and Immunity, University College London, London, UK.
³ Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA; QBI Coronavirus Research Group (QCRG), University of California, San Francisco, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA; Gladstone Institute of Data Science and Biotechnology, J. David Gladstone Institutes, San Francisco, CA, USA.
⁴ QBI Coronavirus Research Group (QCRG), University of California, San Francisco, San Francisco, CA, USA; Texas Biomedical Research Institute, San Antonio, TX, USA.
⁵ QBI Coronavirus Research Group (QCRG), University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Division of Infection and Immunity, University College London, London, UK; Epithelial Stem Cell Biology and Regenerative Medicine Laboratory, The Francis Crick Institute, London, UK.
⁷ Division of Infection and Immunity, University College London, London, UK.
⁸ MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, UK.
⁹ QBI Coronavirus Research Group (QCRG), University of California, San Francisco, San Francisco, CA, USA; Gladstone Institute of Data Science and Biotechnology, J. David Gladstone Institutes, San Francisco, CA, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.
¹⁰ School of Computer Science, Tel Aviv University, Tel Aviv, Israel.
¹¹ School of Electrical Engineering, Tel Aviv University, Tel Aviv, Israel.
¹² COVID Surveillance Unit, The Francis Crick Institute, London, UK.
¹³ QBI Coronavirus Research Group (QCRG), University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, UK; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Saffron Walden, UK.
¹⁵ QBI Coronavirus Research Group (QCRG), University of California, San Francisco, San Francisco, CA, USA.
¹⁶ QBI Coronavirus Research Group (QCRG), University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁷ QBI Coronavirus Research Group (QCRG), University of California, San Francisco, San Francisco, CA, USA; West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, Accra, Ghana; Department of Biochemistry, Cell and Molecular Biology, College of Basic and Applied Sciences, University of Ghana, Accra, Ghana.
¹⁸ Huffington Center for Cell-based Research in Parkinson's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁹ Synthego Corporation, Redwood City, CA, USA.
²⁰ Pharma Mar S.A, Madrid, Spain.
²¹ MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²² Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA; QBI Coronavirus Research Group (QCRG), University of California, San Francisco, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
²³ QBI Coronavirus Research Group (QCRG), University of California, San Francisco, San Francisco, CA, USA; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, UK; Institute of Molecular Systems Biology, Department of Biology, ETH Zürich, Zurich, Switzerland.
²⁴ QBI Coronavirus Research Group (QCRG), University of California, San Francisco, San Francisco, CA, USA; Gladstone Institute of Data Science and Biotechnology, J. David Gladstone Institutes, San Francisco, CA, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA; Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, USA; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA; California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, CA, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
²⁵ QBI Coronavirus Research Group (QCRG), University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: adolfo.garcia-sastre@mssm.edu.
²⁶ QBI Coronavirus Research Group (QCRG), University of California, San Francisco, San Francisco, CA, USA; Division of Infection and Immunity, University College London, London, UK. Electronic address: c.jolly@ucl.ac.uk.
²⁷ Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA; QBI Coronavirus Research Group (QCRG), University of California, San Francisco, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA; Gladstone Institute of Data Science and Biotechnology, J. David Gladstone Institutes, San Francisco, CA, USA. Electronic address: lzulianialvarez@gmail.com.
²⁸ QBI Coronavirus Research Group (QCRG), University of California, San Francisco, San Francisco, CA, USA; Division of Infection and Immunity, University College London, London, UK. Electronic address: g.towers@ucl.ac.uk.
²⁹ Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA; QBI Coronavirus Research Group (QCRG), University of California, San Francisco, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA; Gladstone Institute of Data Science and Biotechnology, J. David Gladstone Institutes, San Francisco, CA, USA. Electronic address: nevan.krogan@ucsf.edu.

PMID: 37738970
PMCID: PMC10604369 (available on 2024-10-12)
DOI: 10.1016/j.cell.2023.08.026

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.

Keywords: SARS-CoV-2; innate immunity; protein-protein interactions; proteomics; systems biology; transcriptomics; variants; virus-host interactions.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

COVID-19* / virology
Humans
Immunity, Innate / genetics
Pandemics
SARS-CoV-2* / genetics

Supplementary concepts

SARS-CoV-2 variants

Abstract

Publication types

MeSH terms

Supplementary concepts

Grants and funding