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

Wilhelm Salmen, Liya Hu, Marina Bok, Natthawan Chaimongkol, Khalil Ettayebi, Stanislav V. Sosnovtsev, Kaundal Soni, B. Vijayalakshmi Ayyar, Sreejesh Shanker, Frederick H. Neill, Banumathi Sankaran, Robert L. Atmar, Mary K. Estes, Kim Y. Green, Viviana Parreño and B. V. Venkataram Prasad ()
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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
Mary K. Estes: 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

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42146-0

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