Global landscape of the host response to SARS-CoV-2 variants reveals viral evolutionary trajectories
Authors: Bouhaddou Mehdi , Reuschl Ann-Kathrin , Polacco Benjamin J. , Thorne Lucy G. , Ummadi Manisha R. , Ye Chengjin , Rosales Romel , Pelin Adrian , Batra Jyoti , Jang Gwendolyn M. , Xu Jiewei , Moen Jack M. , Richards Alicia , Zhou Yuan , Harjai Bhavya , Stevenson Erica , Rojc Ajda , Ragazzini Roberta , Whelan Matthew V.X. , Furnon Wilhelm , De Lorenzo Giuditta , Cowton Vanessa , Syed Abdullah M. , Ciling Alison , Deutsch Noa , Pirak Daniel , Dowgier Giulia , Mesner Dejan , Turner Jane L. , McGovern Briana L. , Rodriguez M. Luis , Leiva-Rebollo Rocio , Dunham Alistair S. , Zhong Xiaofang , Eckhardt Manon , Fossati Andrea , Liotta Nicholas , Kehrer Thomas , Cupic Anastasija , Rutkowska Magda , Mena Nacho , Aslam Sadaf , Hoffert Alyssa , Foussard Helene , Pham John , Lyons Molly , Donahue Laura , Griffin Aliesha , Nugent Rebecca , Holden Kevin , Deans Robert , Aviles Pablo , López-Martín José Antonio , Jimeno Jose M. , Obernier Kirsten , Fabius Jacqueline M. , Soucheray Margaret , Hüttenhain Ruth , Jungreis Irwin , Kellis Manolis , Echeverria Ignacia , Verba Kliment , Bonfanti Paola , Beltrao Pedro , Sharan Roded , Doudna Jennifer A. , Martinez-Sobrido Luis , Patel Arvind , Palmarini Massimo , Miorin Lisa , White Kris , Swaney Danielle L. , García-Sastre Adolfo , Jolly Clare , Zuliani-Alvarez Lorena , Towers Greg J. , Krogan Nevan J. 
Published: October 2022

ABSTRACTA series of SARS-CoV-2 variants of concern (VOCs) have evolved in humans during the COVID-19 pandemic—Alpha, Beta, Gamma, Delta, and Omicron. Here, we used global proteomic and genomic analyses during infection to understand the molecular responses driving VOC evolution. We discovered VOC-specific differences in viral RNA and protein expression levels, including for N, Orf6, and Orf9b, and pinpointed several viral mutations responsible. An analysis of the host response to VOC infection and comprehensive interrogation of altered virus-host protein-protein interactions revealed conserved and divergent regulation of biological pathways. For example, regulation of host translation was highly conserved, consistent with suppression of VOC replication in mice using the translation inhibitor plitidepsin. Conversely, modulation of the host inflammatory response was most divergent, where we found Alpha and Beta, but not Omicron BA.1, antagonized interferon stimulated genes (ISGs), a phenotype that correlated with differing levels of Orf6. Additionally, Delta more strongly upregulated proinflammatory genes compared to other VOCs. Systematic comparison of Omicron subvariants revealed BA.5 to have evolved enhanced ISG and proinflammatory gene suppression that similarly correlated with Orf6 expression, effects not seen in BA.4 due to a mutation that disrupts the Orf6-nuclear pore interaction. Our findings describe how VOCs have evolved to fine-tune viral protein expression and protein-protein interactions to evade both innate and adaptive immune responses, offering a likely explanation for increased transmission in humans.One sentence summarySystematic proteomic and genomic analyses of SARS-CoV-2 variants of concern reveal how variant-specific mutations alter viral gene expression, virus-host protein complexes, and the host response to infection with applications to therapy and future pandemic preparedness.