Signatures of omicron-like adaptation in early SARS-CoV-2 variants and chronic infection

Signatures of omicron-like adaptation in early SARS-CoV-2 variants and chronic infection

Summary: Persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are a source of new variants and can provide insight into evolutionary trajectories. Here, we observe upper airway-specific evolution of SARS-CoV-2, demonstrating a fusion peptide (FP) domain mutation (S:P812...

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Main Authors: Mark Tsz Kin Cheng, Mazharul Altaf, Jesu Castin, Ann-Kathrin Reuschl, Benjamin L. Sievers, Kimia Kamelian, Dejan Mesner, Rebecca B. Morse, Adam Abdullahi, Bo Meng, Kata Csiba, Steven A. Kemp, Darren P. Martin, Clare Jolly, Christopher Ruis, Lipi Thukral, Ravindra K. Gupta
Format: Article
Language:English
Published: Elsevier 2025-08-01
Series:Cell Reports
Subjects:
CP: Microbiology
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124725009064
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Summary:Summary: Persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are a source of new variants and can provide insight into evolutionary trajectories. Here, we observe upper airway-specific evolution of SARS-CoV-2, demonstrating a fusion peptide (FP) domain mutation (S:P812S) adjacent to the S2′ cleavage site that emerged during a chronic infection. Indeed, this mutation had emerged previously and been transmitted in a delta variant lineage. P812S in a spike-pseudotyped virus did not impact entry efficiency. However, cleavage at S1/S2 was reduced, and molecular dynamics simulation demonstrated altered S1/S2 loop conformations. Consistent with impaired S1/S2 cleavage, and reminiscent of Omicron BA.1, cell-cell fusogenicity was severely impaired by P812S. P812S conferred evasion of a FP-targeting monoclonal antibody, consistent with FP-region structural rearrangements. Finally, P812S-bearing viruses showed evasion of polyclonal neutralizing antibodies in sera from vaccinated individuals at 32C. These data shed light on the balance between SARS-CoV-2 upper airway adaptation/immune evasion, syncytium formation, and pathogenic potential.
ISSN:2211-1247

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