SARS-CoV-2 Variants Evolve Convergent Strategies to Remodel the Host Response

Abstract

More transmissible SARS-CoV-2 variants of concern (VOCs) emerged during the COVID-19 pandemic. Here, we used global proteomic and genomic approaches to study the host responses driving VOC evolution. We discovered VOCs evolved convergent strategies to remodel the host response by modulating viral RNA and protein levels, altering nucleocapsid phosphorylation, and rewiring virus-host protein-protein interactions. Integrative systems analysis revealed that although Alpha, Beta, Gamma, and Delta ultimately converged in the suppression of interferon stimulated genes (ISGs), Omicron BA.1 did not, which correlated with increased expression of viral innate immune antagonist proteins Orf6, N, and Orf9b. We observed convergent evolution of enhanced innate immune suppression for Omicron subvariants; BA.5 evolved enhanced innate immune antagonism, which similarly correlated with Orf6 expression, effects muted for BA.4 due a mutation that disrupts the Orf6-nuclear pore interaction. Collectively, our findings lay the groundwork to understand future coronavirus evolution and enhanced human-to-human transmission.

Funding Information: This work has been funded by: National Institutes of Health grant U19AI171110 (NJK), National Institutes of Health grant U19AI135990 (NJK), National Institutes of Health grant U19AI135972 (NJK, AG-S), National Institutes of Health grant R21AI159666 (JAD), National Institutes of Health grant K99AI163868 (MB, Defense Advanced Research Projects Agency (DARPA) Cooperative Agreement #HR0011-19- 2-0020 (NJK, AG-S), Laboratory for Genomics Research (LGR) Excellence in Research Award #133122P (NJK) F. Hoffmann-La Roche (NJK) Vir Biotechnology (NJK). Gifts from QCRG philanthropic donors (NJK) Pharmamar (AG-S, KW). This work was also partly supported by CRIPT (Center for Research on Influenza Pathogenesis and Transmission), a NIAID funded Center of Excellence for Influenza Research and Response (CEIRR, contract # 75N93021C00014) and by NIAID grant U19AI142733, NCI Seronet grant U54CA260560, the JPB and OPP foundations and an anonymous philanthropic donor to AG-S. Department of Defense W81XWH2110103 (LMS) Department of Defense W81XWH2110095 (LMS). National Institutes of Health grant 1R43AI165089-01 (LMS). National Institutes of Health grant 1R01AI161363-01 (LMS). National Institutes of Health grant 1R01AI161175-01A1 (LMS) National Institutes of Health contract number 75N93021C00014 (LMS). San Antonio Partnership for Precision Therapeutics (LMS). San Antonio Medical Foundation (LMS). Marie Skłodowska-Curie Individual Fellowships no. 896014 (RR). European Research Council (ERC-Stg no. 639429) (PB). The Rosetrees Trust (M362-F1; M553) (PB). NIHR GOSH BRC (PB) CF Trust (SRC006; SRC020) (PB) Wellcome Investigator Award 223065 (CJ). Wellcome Investigator Award 220863 and Wellcome Collaborative Award 214344(GJT) MRC/UKRI G2P-UK National Virology consortium (MR/W005611/1) (GJT, CJ).

Declaration of Interests: The Krogan Laboratory has received research support from Vir Biotechnology, F. Hoffmann-La Roche, and Rezo Therapeutics. Nevan Krogan has financially compensated consulting agreements with the Icahn School of Medicine at Mount Sinai, New York, Maze Therapeutics, Interline Therapeutics, Rezo Therapeutics, GEn1E Lifesciences, Inc. and Twist Bioscience Corp. He is on the Board of Directors of Rezo Therapeutics and is a shareholder in Tenaya Therapeutics, Maze Therapeutics, Rezo Therapeutics, and Interline Therapeutics. The A.G.-S. laboratory has received research support from Pfizer, Senhwa Biosciences, Kenall Manufacturing, Blade Therapeutics, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, Atea Pharma, Applied Biological Laboratories and Merck. A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Castlevax, Amovir, Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Vaxalto, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories, Pharmamar, Paratus, CureLab Oncology, CureLab Veterinary, Synairgen and Pfizer. A.G.-S. has been an invited speaker in meeting events organized by Seqirus, Janssen, Abbott and Astrazeneca. A.G.-S. is inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer, owned by the Icahn School of Medicine at Mount Sinai, New York. MB is a financially compensated scientific advisor for GEn1E Lifesciences. C.Y and L. M.-S are co-inventors on a patent application directed to reverse genetics approaches to generate recombinant SARS-CoV-2. INCOMPLETE

Ethics Approval Statement: All work was conducted under protocols approved by the Institutional Animal Care and Use Committee (IACUC) at the Icahn school of Medicine in Mount Sinai Hospital, New York City.

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