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A single nanobody neutralizes multiple epochally evolving human noroviruses by modulating capsid plasticity

Author

Listed:
  • Wilhelm Salmen

    (Baylor College of Medicine)

  • Liya Hu

    (Baylor College of Medicine)

  • Marina Bok

    (Virology Institute and Technology Innovation, IVIT, CONICET-INTA)

  • Natthawan Chaimongkol

    (National Institutes of Health)

  • Khalil Ettayebi

    (Baylor College of Medicine)

  • Stanislav V. Sosnovtsev

    (National Institutes of Health)

  • Kaundal Soni

    (Baylor College of Medicine)

  • B. Vijayalakshmi Ayyar

    (Baylor College of Medicine)

  • Sreejesh Shanker

    (Baylor College of Medicine)

  • Frederick H. Neill

    (Baylor College of Medicine)

  • Banumathi Sankaran

    (Lawrence Berkeley Laboratory)

  • Robert L. Atmar

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Mary K. Estes

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Kim Y. Green

    (National Institutes of Health)

  • Viviana Parreño

    (Virology Institute and Technology Innovation, IVIT, CONICET-INTA)

  • B. V. Venkataram Prasad

    (Baylor College of Medicine
    Baylor College of Medicine)

Abstract

Acute gastroenteritis caused by human noroviruses (HuNoVs) is a significant global health and economic burden and is without licensed vaccines or antiviral drugs. The GII.4 HuNoV causes most epidemics worldwide. This virus undergoes epochal evolution with periodic emergence of variants with new antigenic profiles and altered specificity for histo-blood group antigens (HBGA), the determinants of cell attachment and susceptibility, hampering the development of immunotherapeutics. Here, we show that a llama-derived nanobody M4 neutralizes multiple GII.4 variants with high potency in human intestinal enteroids. The crystal structure of M4 complexed with the protruding domain of the GII.4 capsid protein VP1 revealed a conserved epitope, away from the HBGA binding site, fully accessible only when VP1 transitions to a “raised” conformation in the capsid. Together with dynamic light scattering and electron microscopy of the GII.4 VLPs, our studies suggest a mechanism in which M4 accesses the epitope by altering the conformational dynamics of the capsid and triggering its disassembly to neutralize GII.4 infection.

Suggested Citation

  • Wilhelm Salmen & Liya Hu & Marina Bok & Natthawan Chaimongkol & Khalil Ettayebi & Stanislav V. Sosnovtsev & Kaundal Soni & B. Vijayalakshmi Ayyar & Sreejesh Shanker & Frederick H. Neill & Banumathi Sa, 2023. "A single nanobody neutralizes multiple epochally evolving human noroviruses by modulating capsid plasticity," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42146-0
    DOI: 10.1038/s41467-023-42146-0
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    References listed on IDEAS

    as
    1. Sarah M Bartsch & Benjamin A Lopman & Sachiko Ozawa & Aron J Hall & Bruce Y Lee, 2016. "Global Economic Burden of Norovirus Gastroenteritis," PLOS ONE, Public Library of Science, vol. 11(4), pages 1-16, April.
    2. Liya Hu & Wilhelm Salmen & Rong Chen & Yi Zhou & Frederick Neill & James E. Crowe & Robert L. Atmar & Mary K. Estes & B. V. Venkataram Prasad, 2022. "Atomic structure of the predominant GII.4 human norovirus capsid reveals novel stability and plasticity," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Gabriela Alvarado & Wilhelm Salmen & Khalil Ettayebi & Liya Hu & Banumathi Sankaran & Mary K. Estes & B. V. Venkataram Prasad & James E. Crowe, 2021. "Broadly cross-reactive human antibodies that inhibit genogroup I and II noroviruses," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    4. B. Vijayalakshmi Ayyar & Khalil Ettayebi & Wilhelm Salmen & Umesh C. Karandikar & Frederick H. Neill & Victoria R. Tenge & Sue E. Crawford & Erhard Bieberich & B. V. Venkataram Prasad & Robert L. Atma, 2023. "CLIC and membrane wound repair pathways enable pandemic norovirus entry and infection," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
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