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Peer-reviewedCC BY-NC-NDNature Communications

Loss-of-function mutation in Omicron variants reduces spike protein expression and attenuates SARS-CoV-2 infection

  • Michelle N. Vu1,2
  • R. Elias Alvarado1,3,4,2
  • Dorothea R. Morris1,5,2,6
  • Kumari G. Lokugamage1,7,8,2
  • Yiyang Zhou1,7,8,9
  • Angelica L. Morgan1,7,8,10
  • Yani P. Ahearn1,2
  • Nicholas C. Hazell1,11,2
  • Leah K. Estes1,2
  • Alyssa M. McLeland1,12,2,13
  • Craig Schindewolf1,2
  • Jessica A. Plante1,14,15,10
11 more authors
  • William M. Meyers11,2
  • Jordan T. Murray1
  • Patricia A. Crocquet-Valdes11,16,12,2,13
  • Scott C. Weaver1,14,15,16,10
  • Mehul S. Suthar7,8,9
  • David Hughes Walker17,11,9
  • William K. Russell18,12,2,13
  • Andrew L. Routh19,16,12,2,13
  • Haitao Hu17,1,11,20
  • Kenneth S. Plante1,11,14
  • Vineet D. Menachery21,22,23,24
24 affiliations
  1. 1Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA
  2. 2Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States
  3. 3Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX, USA
  4. 4Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX, United States
  5. 5Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, USA
  6. 6Pediatrics, University of Texas Medical Branch, Galveston, TX, United States
  7. 7Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
  8. 8Emory Vaccine Center, Emory University, Atlanta, GA, USA
  9. 9Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, United States
  10. 10Pathology, University of Texas Medical Branch, Galveston, TX, United States
  11. 11Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA
  12. 12Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, TX, United States
  13. 13World Reference Center of Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, United States
  14. 14Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA
  15. 15World Reference Center of Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA
  16. 16Center for Biodefense and Emerging Infectious Disease, University of Texas Medical Branch, Galveston, TX, United States
  17. 17Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX, USA
  18. 18Department of Biochemistry and Microbiology, University of Texas Medical Branch, Galveston, TX, USA
  19. 19Department of Microbiology and Immunology, Scripps Research, La Jolla, CA, USA
  20. 20Institute of Microbiology, Chinese Academy of Sciences, Beijing, PR China
  21. 21Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA. [email protected]
  22. 22Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA. [email protected]
  23. 23Emory Vaccine Center, Emory University, Atlanta, GA, USA. [email protected]
  24. 24Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA. [email protected]
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Abstract

SARS-CoV-2 Omicron variants emerged in 2022 with >30 novel mutations in the spike alone. While most studies focus on receptor binding domain changes, mutations in the C-terminus of S1 (CTS1), adjacent to the furin cleavage site, have largely been ignored. Here, we examine three Omicron mutations in CTS1: H655Y, N679K, and P681H. Generating a SARS-CoV-2 triple mutant (YKH), we find that the mutant increases spike processing, consistent with prior reports for H655Y/P681H. In addition, the YKH mutant induces attenuated disease, but augments viral loads in male golden Syrian hamsters. Next, we generate a single N679K mutant, finding it reduces viral replication in Calu3 human respiratory cells and induces less disease in male golden Syrian hamsters. Mechanistically, the N679K mutant has increased spike processing but also reduces spike in purified virions; spike decreases are further exacerbated in infected Calu3 cell lysates. Importantly, exogenous spike expression reveals that N679K reduces overall spike protein in the context of the epidemic strain. Although a loss-of-function mutation, transmission competition demonstrates that N679K confers a replication advantage in the upper airway, potentially impacting transmissibility. Together, the data show that N679K reduces overall spike protein during Omicron infection, which has implications for infection, immunity, and transmission.

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Cite

BibTeXRIS
BibTeX
@article{vu2026lossoffunction,
  title = {{Loss-of-function mutation in Omicron variants reduces spike protein expression and attenuates SARS-CoV-2 infection}},
  author = {Michelle N. Vu and R. Elias Alvarado and Dorothea R. Morris and Kumari G. Lokugamage and Yiyang Zhou and Angelica L. Morgan and Yani P. Ahearn and Nicholas C. Hazell and Leah K. Estes and Alyssa M. McLeland and Craig Schindewolf and Jessica A. Plante and William M. Meyers and Jordan T. Murray and Patricia A. Crocquet-Valdes and Scott C. Weaver and Mehul S. Suthar and David Hughes Walker and William K. Russell and Andrew L. Routh and Haitao Hu and Kenneth S. Plante and Vineet D. Menachery},
  journal = {Nature Communications},
  year = {2026},
  month = aug,
  doi = {10.1038/s41467-026-76680-4},
  url = {https://doi.org/10.1038/s41467-026-76680-4},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Loss-of-function mutation in Omicron variants reduces spike protein expression and attenuates SARS-CoV-2 infection
AU  - Michelle N. Vu
AU  - R. Elias Alvarado
AU  - Dorothea R. Morris
AU  - Kumari G. Lokugamage
AU  - Yiyang Zhou
AU  - Angelica L. Morgan
AU  - Yani P. Ahearn
AU  - Nicholas C. Hazell
AU  - Leah K. Estes
AU  - Alyssa M. McLeland
AU  - Craig Schindewolf
AU  - Jessica A. Plante
AU  - William M. Meyers
AU  - Jordan T. Murray
AU  - Patricia A. Crocquet-Valdes
AU  - Scott C. Weaver
AU  - Mehul S. Suthar
AU  - David Hughes Walker
AU  - William K. Russell
AU  - Andrew L. Routh
AU  - Haitao Hu
AU  - Kenneth S. Plante
AU  - Vineet D. Menachery
PY  - 2026
DA  - 2026/08/12
JO  - Nature Communications
DO  - 10.1038/s41467-026-76680-4
UR  - https://doi.org/10.1038/s41467-026-76680-4
AB  - SARS-CoV-2 Omicron variants emerged in 2022 with >30 novel mutations in the spike alone. While most studies focus on receptor binding domain changes, mutations in the C-terminus of S1 (CTS1), adjacent to the furin cleavage site, have largely been ignored. Here, we examine three Omicron mutations in CTS1: H655Y, N679K, and P681H. Generating a SARS-CoV-2 triple mutant (YKH), we find that the mutant increases spike processing, consistent with prior reports for H655Y/P681H. In addition, the YKH mutant induces attenuated disease, but augments viral loads in male golden Syrian hamsters. Next, we generate a single N679K mutant, finding it reduces viral replication in Calu3 human respiratory cells and induces less disease in male golden Syrian hamsters. Mechanistically, the N679K mutant has increased spike processing but also reduces spike in purified virions; spike decreases are further exacerbated in infected Calu3 cell lysates. Importantly, exogenous spike expression reveals that N679K reduces overall spike protein in the context of the epidemic strain. Although a loss-of-function mutation, transmission competition demonstrates that N679K confers a replication advantage in the upper airway, potentially impacting transmissibility. Together, the data show that N679K reduces overall spike protein during Omicron infection, which has implications for infection, immunity, and transmission.
SN  - 2041-1723
ER  -