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Cell
. 2023 Sep 19;S0092-8674(23)00915-7.
doi: 10.1016/j.cell.2023.08.026. Online ahead of print. SARS-CoV-2 variants evolve convergent strategies to remodel the host response
Mehdi Bouhaddou 1 , Ann-Kathrin Reuschl 2 , Benjamin J Polacco 3 , Lucy G Thorne 2 , Manisha R Ummadi 3 , Chengjin Ye 4 , Romel Rosales 5 , Adrian Pelin 3 , Jyoti Batra 3 , Gwendolyn M Jang 3 , Jiewei Xu 3 , Jack M Moen 3 , Alicia L Richards 3 , Yuan Zhou 3 , Bhavya Harjai 3 , Erica Stevenson 3 , Ajda Rojc 3 , Roberta Ragazzini 6 , Matthew V X Whelan 7 , Wilhelm Furnon 8 , Giuditta De Lorenzo 8 , Vanessa Cowton 8 , Abdullah M Syed 9 , Alison Ciling 9 , Noa Deutsch 10 , Daniel Pirak 11 , Giulia Dowgier 12 , Dejan Mesner 7 , Jane L Turner 7 , Briana L McGovern 13 , M Luis Rodriguez 13 , Rocio Leiva-Rebollo 5 , Alistair S Dunham 14 , Xiaofang Zhong 3 , Manon Eckhardt 3 , Andrea Fossati 3 , Nicholas F Liotta 15 , Thomas Kehrer 16 , Anastasija Cupic 16 , Magdalena Rutkowska 16 , Ignacio Mena 5 , Sadaf Aslam 5 , Alyssa Hoffert 3 , Helene Foussard 3 , Charles Ochieng' Olwal 17 , Weiqing Huang 18 , Thomas Zwaka 18 , John Pham 19 , Molly Lyons 19 , Laura Donohue 19 , Aliesha Griffin 19 , Rebecca Nugent 19 , Kevin Holden 19 , Robert Deans 19 , Pablo Aviles 20 , Jose A Lopez-Martin 20 , Jose M Jimeno 20 , Kirsten Obernier 3 , Jacqueline M Fabius 3 , Margaret Soucheray 3 , Ruth Hüttenhain 3 , Irwin Jungreis 21 , Manolis Kellis 21 , Ignacia Echeverria 22 , Kliment Verba 22 , Paola Bonfanti 6 , Pedro Beltrao 23 , Roded Sharan 10 , Jennifer A Doudna 24 , Luis Martinez-Sobrido 4 , Arvind H Patel 8 , Massimo Palmarini 8 , Lisa Miorin 5 , Kris White 5 , Danielle L Swaney 3 , Adolfo Garcia-Sastre 25 , Clare Jolly 26 , Lorena Zuliani-Alvarez 27 , Greg J Towers 28 , Nevan J Krogan 29
Affiliations
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.
. 2023 Sep 19;S0092-8674(23)00915-7.
doi: 10.1016/j.cell.2023.08.026. Online ahead of print. SARS-CoV-2 variants evolve convergent strategies to remodel the host response
Mehdi Bouhaddou 1 , Ann-Kathrin Reuschl 2 , Benjamin J Polacco 3 , Lucy G Thorne 2 , Manisha R Ummadi 3 , Chengjin Ye 4 , Romel Rosales 5 , Adrian Pelin 3 , Jyoti Batra 3 , Gwendolyn M Jang 3 , Jiewei Xu 3 , Jack M Moen 3 , Alicia L Richards 3 , Yuan Zhou 3 , Bhavya Harjai 3 , Erica Stevenson 3 , Ajda Rojc 3 , Roberta Ragazzini 6 , Matthew V X Whelan 7 , Wilhelm Furnon 8 , Giuditta De Lorenzo 8 , Vanessa Cowton 8 , Abdullah M Syed 9 , Alison Ciling 9 , Noa Deutsch 10 , Daniel Pirak 11 , Giulia Dowgier 12 , Dejan Mesner 7 , Jane L Turner 7 , Briana L McGovern 13 , M Luis Rodriguez 13 , Rocio Leiva-Rebollo 5 , Alistair S Dunham 14 , Xiaofang Zhong 3 , Manon Eckhardt 3 , Andrea Fossati 3 , Nicholas F Liotta 15 , Thomas Kehrer 16 , Anastasija Cupic 16 , Magdalena Rutkowska 16 , Ignacio Mena 5 , Sadaf Aslam 5 , Alyssa Hoffert 3 , Helene Foussard 3 , Charles Ochieng' Olwal 17 , Weiqing Huang 18 , Thomas Zwaka 18 , John Pham 19 , Molly Lyons 19 , Laura Donohue 19 , Aliesha Griffin 19 , Rebecca Nugent 19 , Kevin Holden 19 , Robert Deans 19 , Pablo Aviles 20 , Jose A Lopez-Martin 20 , Jose M Jimeno 20 , Kirsten Obernier 3 , Jacqueline M Fabius 3 , Margaret Soucheray 3 , Ruth Hüttenhain 3 , Irwin Jungreis 21 , Manolis Kellis 21 , Ignacia Echeverria 22 , Kliment Verba 22 , Paola Bonfanti 6 , Pedro Beltrao 23 , Roded Sharan 10 , Jennifer A Doudna 24 , Luis Martinez-Sobrido 4 , Arvind H Patel 8 , Massimo Palmarini 8 , Lisa Miorin 5 , Kris White 5 , Danielle L Swaney 3 , Adolfo Garcia-Sastre 25 , Clare Jolly 26 , Lorena Zuliani-Alvarez 27 , Greg J Towers 28 , Nevan J Krogan 29
Affiliations
- PMID: 37738970
- DOI: 10.1016/j.cell.2023.08.026
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.