A Single Nanobody Neutralizes Multiple Epochally Evolving Human Noroviruses by Modulating Capsid Plasticity

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Oct 16

PMID 37845211

Authors

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 Parreno

B V Venkataram Prasad

Affiliations

Soon will be listed here.

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.

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