Signatures of omicron-like adaptation in early SARS-CoV-2 variants and chronic infection
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.
Authors
- Kimia Kamelian (ORCID: https://orcid.org/0000-0003-3465-1285)
- Lipi Thukral (ORCID: https://orcid.org/0000-0002-1961-039X)
- Adam Abdullahi (ORCID: https://orcid.org/0000-0001-9703-8264)
- Ravindra K. Gupta (ORCID: https://orcid.org/0000-0001-9751-1808)
- Mark T. K. Cheng (ORCID: https://orcid.org/0000-0003-4323-5574)
- Dejan Mesner (ORCID: https://orcid.org/0000-0002-7109-4011)
- Ann‐Kathrin Reuschl (ORCID: https://orcid.org/0000-0002-1459-3519)
- Steven A. Kemp (ORCID: https://orcid.org/0000-0001-7077-6793)
- Benjamín L. Sievers (ORCID: https://orcid.org/0000-0002-9681-9082)
- Clare Jolly (ORCID: https://orcid.org/0000-0002-4603-2281)
- Rebecca Morse (ORCID: https://orcid.org/0009-0001-0088-8009)
- Kata Csiba
- Bo Meng (ORCID: https://orcid.org/0000-0001-5668-2221)
- Jesu Castin
- Christopher Ruis
- Mazharul Altaf
- Darren P. Martin
Institutions
- University of Cape Town (ZA)
- Institute of Genomics and Integrative Biology (IN)
- University of Cambridge (GB)
- Bridge University (SS)
- Africa Health Research Institute (ZA)
- Wellcome Centre for Infectious Diseases Research in Africa (ZA)
- University College London (GB)
- Academy of Scientific and Innovative Research (IN)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-08-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.116135
- Citations
- 1
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 1.40
Funders
- Wellcome Trust
- National Institute for Health and Care Research
- Department of Health and Social Care
- Department of Biotechnology, Ministry of Science and Technology, India
- The Wellcome Trust DBT India Alliance
- NIHR Cambridge Biomedical Research Centre