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

Da-Yuan Chen, Chue Vin Chin, Devin Kenney, Alexander H. Tavares, Nazimuddin Khan, Hasahn L. Conway, GuanQun Liu, Manish C. Choudhary, Hans P. Gertje, Aoife K. O’Connell, Scott Adams, Darrell N. Kotton, Alexandra Herrmann, Armin Ensser, John H. Connor, Markus Bosmann, Jonathan Z. Li, Michaela U. Gack, Susan C. Baker, Robert N. Kirchdoerfer, Yachana Kataria, Nicholas A. Crossland, Florian Douam and Mohsan Saeed ()
Additional contact information
Da-Yuan Chen: Boston University Chobanian and Avedisian School of Medicine
Chue Vin Chin: Boston University Chobanian and Avedisian School of Medicine
Devin Kenney: Boston University
Alexander H. Tavares: Boston University Chobanian and Avedisian School of Medicine
Nazimuddin Khan: Boston University Chobanian and Avedisian School of Medicine
Hasahn L. Conway: Boston University Chobanian and Avedisian School of Medicine
GuanQun Liu: Cleveland Clinic
Manish C. Choudhary: Brigham and Women’s Hospital
Hans P. Gertje: Boston University
Aoife K. O’Connell: Boston University
Scott Adams: Boston University
Darrell N. Kotton: Center for Regenerative Medicine of Boston University and Boston Medical Center
Alexandra Herrmann: University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg
Armin Ensser: University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg
John H. Connor: Boston University
Markus Bosmann: Boston University Chobanian and Avedisian School of Medicine
Jonathan Z. Li: Brigham and Women’s Hospital
Michaela U. Gack: Cleveland Clinic
Susan C. Baker: Loyola University Chicago
Robert N. Kirchdoerfer: University of Wisconsin-Madison
Yachana Kataria: Boston University Chobanian and Avedisian School of Medicine
Nicholas A. Crossland: Boston University
Florian Douam: Boston University
Mohsan Saeed: Boston University Chobanian and Avedisian School of Medicine

Nature, 2023, vol. 615, issue 7950, 143-150

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-05697-2

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