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Functional and antigenic characterization of SARS-CoV-2 spike fusion peptide by deep mutational scanning

Author

Listed:
  • Ruipeng Lei

    (University of Illinois at Urbana-Champaign)

  • Enya Qing

    (Loyola University Chicago)

  • Abby Odle

    (University of Iowa)

  • Meng Yuan

    (The Scripps Research Institute)

  • Chaminda D. Gunawardene

    (Rutgers New Jersey Medical School
    Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School)

  • Timothy J. C. Tan

    (University of Illinois at Urbana-Champaign)

  • Natalie So

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Wenhao O. Ouyang

    (University of Illinois at Urbana-Champaign)

  • Ian A. Wilson

    (The Scripps Research Institute
    The Scripps Research Institute)

  • Tom Gallagher

    (Loyola University Chicago)

  • Stanley Perlman

    (University of Iowa
    University of Iowa)

  • Nicholas C. Wu

    (University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Lok-Yin Roy Wong

    (University of Iowa
    Rutgers New Jersey Medical School
    Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School)

Abstract

The fusion peptide of SARS-CoV-2 spike protein is functionally important for membrane fusion during virus entry and is part of a broadly neutralizing epitope. However, sequence determinants at the fusion peptide and its adjacent regions for pathogenicity and antigenicity remain elusive. In this study, we perform a series of deep mutational scanning (DMS) experiments on an S2 region spanning the fusion peptide of authentic SARS-CoV-2 in different cell lines and in the presence of broadly neutralizing antibodies. We identify mutations at residue 813 of the spike protein that reduced TMPRSS2-mediated entry with decreased virulence. In addition, we show that an F823Y mutation, present in bat betacoronavirus HKU9 spike protein, confers resistance to broadly neutralizing antibodies. Our findings provide mechanistic insights into SARS-CoV-2 pathogenicity and also highlight a potential challenge in developing broadly protective S2-based coronavirus vaccines.

Suggested Citation

  • Ruipeng Lei & Enya Qing & Abby Odle & Meng Yuan & Chaminda D. Gunawardene & Timothy J. C. Tan & Natalie So & Wenhao O. Ouyang & Ian A. Wilson & Tom Gallagher & Stanley Perlman & Nicholas C. Wu & Lok-Y, 2024. "Functional and antigenic characterization of SARS-CoV-2 spike fusion peptide by deep mutational scanning," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48104-8
    DOI: 10.1038/s41467-024-48104-8
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    References listed on IDEAS

    as
    1. Lukas Wettstein & Tatjana Weil & Carina Conzelmann & Janis A. Müller & Rüdiger Groß & Maximilian Hirschenberger & Alina Seidel & Susanne Klute & Fabian Zech & Caterina Prelli Bozzo & Nico Preising & G, 2021. "Alpha-1 antitrypsin inhibits TMPRSS2 protease activity and SARS-CoV-2 infection," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
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