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