Multiple signals in the gut contract the mouse norovirus capsid to block antibody binding while enhancing receptor affinity

Alexis N. Williams, Michael B. Sherman, Hong Q. Smith, Stefan Taube, B. Montgomery Pettitt, Christiane E. Wobus, Thomas J. Smith

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Human norovirus is the leading cause of gastroenteritis worldwide, with no approved vaccine or antiviral treatment to mitigate infection. These plus-strand RNA viruses have T = 3 icosahedral protein capsids with 90 pronounced protruding (P) domain dimers, to which antibodies and cellular receptors bind. We previously demonstrated that bile binding to the capsid of mouse norovirus (MNV) causes several major conformational changes; the entire P domain rotates by ~90° and contracts onto the shell, the P domain dimers rotate about each other, and the structural equilibrium of the epitopes at the top of the P domain shifts toward the closed conformation, which favors receptor binding while blocking antibody binding. Here, we demonstrate that MNV undergoes reversible conformational changes at pH 5.0 that are nearly identical to those observed when bile binds. Notably, at low pH or when metals bind, a cluster of acidic resides in the G'-H' loop interact and distort the G'-H' loop, and this may drive C'-D' loop movement toward the closed conformation. Enzyme-linked immunosorbent assays with infectious virus particles at low pH or in the presence of metals demonstrated that all tested antibodies do not bind to this contracted form, akin to what was observed with the MNV-bile complex. Therefore, low pH, cationic metals, and bile salts are physiological triggers in the gut for P domain contraction and structural rearrangement, which synergistically prime the virus for receptor binding while blocking antibody binding.

Original languageEnglish (US)
Article numbere01471-21
JournalJournal of virology
Volume95
Issue number22
DOIs
StatePublished - Nov 2021

Keywords

  • Cryo-EM
  • Monoclonal antibodies
  • Neutralizing antibodies
  • Norovirus
  • Structure

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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