Spike and nsp6 are key determinants of SARS-CoV-2 Omicron BA.1 attenuation

Chen DY, Chin CV, Kenney D, Tavares AH, Khan N, Conway HL, Liu GQ, Choudhary MC, Gertje HP, O’Connell AK, Adams S, Kotton DN, Herrmann A, Enßer A, Connor JH, Bosmann M, Li JZ, Gack MU, Baker SC, Kirchdoerfer RN, Kataria Y, Crossland NA, Douam F, Saeed M (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Nature Nature Research

DOI: 10.1038/s41586-023-05697-2

Abstract

The SARS-CoV-2 Omicron variant is more immune evasive and less virulent than other major viral variants that have so far been recognized1–12. The Omicron spike (S) protein, which has an unusually large number of mutations, is considered to be the main driver of these phenotypes. Here we generated chimeric recombinant SARS-CoV-2 encoding the S gene of Omicron (BA.1 lineage) in the backbone of an ancestral SARS-CoV-2 isolate, and compared this virus with the naturally circulating Omicron variant. The Omicron S-bearing virus robustly escaped vaccine-induced humoral immunity, mainly owing to mutations in the receptor-binding motif; however, unlike naturally occurring Omicron, it efficiently replicated in cell lines and primary-like distal lung cells. Similarly, in K18-hACE2 mice, although virus bearing Omicron S caused less severe disease than the ancestral virus, its virulence was not attenuated to the level of Omicron. Further investigation showed that mutating non-structural protein 6 (nsp6) in addition to the S protein was sufficient to recapitulate the attenuated phenotype of Omicron. This indicates that although the vaccine escape of Omicron is driven by mutations in S, the pathogenicity of Omicron is determined by mutations both in and outside of the S protein.

Authors with CRIS profile

Alexandra Herrmann Institute of Clinical and Molecular Virology Armin Enßer Medizinische Fakultät

Involved external institutions

Boston University US United States (USA) (US) Cleveland Clinic US United States (USA) (US) Loyola University Chicago US United States (USA) (US) Massachusetts General Hospital US United States (USA) (US) Brigham and Women's Hospital (BWH) US United States (USA) (US) University of Wisconsin - Madison US United States (USA) (US)

How to cite

APA:

Chen, D.Y., Chin, C.V., Kenney, D., Tavares, A.H., Khan, N., Conway, H.L.,... Saeed, M. (2023). Spike and nsp6 are key determinants of SARS-CoV-2 Omicron BA.1 attenuation. Nature. https://doi.org/10.1038/s41586-023-05697-2

MLA:

Chen, Da Yuan, et al. "Spike and nsp6 are key determinants of SARS-CoV-2 Omicron BA.1 attenuation." Nature (2023).

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