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

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

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

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 language	English
Pages (from-to)	4597-4614.e26
Journal	Cell
Volume	186
Issue number	21
DOIs	https://doi.org/10.1016/j.cell.2023.08.026
State	Published - 12 Oct 2023

Keywords

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

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10.1016/j.cell.2023.08.026

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Bouhaddou, M., Reuschl, A. K., Polacco, B. J., Thorne, L. G., Ummadi, M. R., Ye, C., Rosales, R., Pelin, A., Batra, J., Jang, G. M., Xu, J., Moen, J. M., Richards, A. L., Zhou, Y., Harjai, B., Stevenson, E., Rojc, A., Ragazzini, R., Whelan, M. V. X., ... Krogan, N. J. (2023). SARS-CoV-2 variants evolve convergent strategies to remodel the host response. Cell, 186(21), 4597-4614.e26. https://doi.org/10.1016/j.cell.2023.08.026

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title = "SARS-CoV-2 variants evolve convergent strategies to remodel the host response",

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",

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

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year = "2023",

month = oct,

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doi = "10.1016/j.cell.2023.08.026",

language = "English",

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Bouhaddou, M, Reuschl, AK, Polacco, BJ, Thorne, LG, Ummadi, MR, Ye, C, Rosales, R, Pelin, A, Batra, J, Jang, GM, Xu, J, Moen, JM, Richards, AL, Zhou, Y, Harjai, B, Stevenson, E, Rojc, A, Ragazzini, R, Whelan, MVX, Furnon, W, De Lorenzo, G, Cowton, V, Syed, AM, Ciling, A, Deutsch, N, Pirak, D, Dowgier, G, Mesner, D, Turner, JL, McGovern, BL, Rodriguez, ML, Leiva-Rebollo, R, Dunham, AS, Zhong, X, Eckhardt, M, Fossati, A, Liotta, NF, Kehrer, T, Cupic, A, Rutkowska, M, Mena, I, Aslam, S, Hoffert, A, Foussard, H, Olwal, CO, Huang, W, Zwaka, T, Pham, J, Lyons, M, Donohue, L, Griffin, A, Nugent, R, Holden, K, Deans, R, Aviles, P, Lopez-Martin, JA, Jimeno, JM, Obernier, K, Fabius, JM, Soucheray, M, Hüttenhain, R, Jungreis, I, Kellis, M, Echeverria, I, Verba, K, Bonfanti, P, Beltrao, P, Sharan, R, Doudna, JA, Martinez-Sobrido, L, Patel, AH, Palmarini, M, Miorin, L, White, K, Swaney, DL, Garcia-Sastre, A, Jolly, C, Zuliani-Alvarez, L, Towers, GJ & Krogan, NJ 2023, 'SARS-CoV-2 variants evolve convergent strategies to remodel the host response', Cell, vol. 186, no. 21, pp. 4597-4614.e26. https://doi.org/10.1016/j.cell.2023.08.026

TY - JOUR

T1 - SARS-CoV-2 variants evolve convergent strategies to remodel the host response

AU - Bouhaddou, Mehdi

AU - Reuschl, Ann Kathrin

AU - Polacco, Benjamin J.

AU - Thorne, Lucy G.

AU - Ummadi, Manisha R.

AU - Ye, Chengjin

AU - Rosales, Romel

AU - Pelin, Adrian

AU - Batra, Jyoti

AU - Jang, Gwendolyn M.

AU - Xu, Jiewei

AU - Moen, Jack M.

AU - Richards, Alicia L.

AU - Zhou, Yuan

AU - Harjai, Bhavya

AU - Stevenson, Erica

AU - Rojc, Ajda

AU - Ragazzini, Roberta

AU - Whelan, Matthew V.X.

AU - Furnon, Wilhelm

AU - De Lorenzo, Giuditta

AU - Cowton, Vanessa

AU - Syed, Abdullah M.

AU - Ciling, Alison

AU - Deutsch, Noa

AU - Pirak, Daniel

AU - Dowgier, Giulia

AU - Mesner, Dejan

AU - Turner, Jane L.

AU - McGovern, Briana L.

AU - Rodriguez, M. Luis

AU - Leiva-Rebollo, Rocio

AU - Dunham, Alistair S.

AU - Zhong, Xiaofang

AU - Eckhardt, Manon

AU - Fossati, Andrea

AU - Liotta, Nicholas F.

AU - Kehrer, Thomas

AU - Cupic, Anastasija

AU - Rutkowska, Magdalena

AU - Mena, Ignacio

AU - Aslam, Sadaf

AU - Hoffert, Alyssa

AU - Foussard, Helene

AU - Olwal, Charles Ochieng’

AU - Huang, Weiqing

AU - Zwaka, Thomas

AU - Pham, John

AU - Lyons, Molly

AU - Donohue, Laura

AU - Griffin, Aliesha

AU - Nugent, Rebecca

AU - Holden, Kevin

AU - Deans, Robert

AU - Aviles, Pablo

AU - Lopez-Martin, Jose A.

AU - Jimeno, Jose M.

AU - Obernier, Kirsten

AU - Fabius, Jacqueline M.

AU - Soucheray, Margaret

AU - Hüttenhain, Ruth

AU - Jungreis, Irwin

AU - Kellis, Manolis

AU - Echeverria, Ignacia

AU - Verba, Kliment

AU - Bonfanti, Paola

AU - Beltrao, Pedro

AU - Sharan, Roded

AU - Doudna, Jennifer A.

AU - Martinez-Sobrido, Luis

AU - Patel, Arvind H.

AU - Palmarini, Massimo

AU - Miorin, Lisa

AU - White, Kris

AU - Swaney, Danielle L.

AU - Garcia-Sastre, Adolfo

AU - Jolly, Clare

AU - Zuliani-Alvarez, Lorena

AU - Towers, Greg J.

AU - Krogan, Nevan J.

PY - 2023/10/12

Y1 - 2023/10/12

N2 - 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.

AB - 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.

KW - SARS-CoV-2

KW - innate immunity

KW - protein-protein interactions

KW - proteomics

KW - systems biology

KW - transcriptomics

KW - variants

KW - virus-host interactions

UR - http://www.scopus.com/inward/record.url?scp=85172999376&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2023.08.026

DO - 10.1016/j.cell.2023.08.026

M3 - Article

C2 - 37738970

AN - SCOPUS:85172999376

SN - 0092-8674

VL - 186

SP - 4597-4614.e26

JO - Cell

JF - Cell

IS - 21

ER -

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

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