# The role of norovirus capsid flexibility in infection and pathogenesis

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $209,535

## Abstract

Title: The role of norovirus capsid flexibility in infection and pathogenesis
Abstract
Virus capsids are metastable structures that transition between a stable form in the environment and an
unstable form inside the host. Specific cues, generally thought to occur at or inside the cell, are required to
elicit this change. This ability of capsids to be flexible is a fundamental feature of virions that is critical for the
success of a virus infection. However, there is a fundamental gap in our understanding how capsid flexibility
influences norovirus infection and pathogenesis. Noroviruses are prevalent enteric pathogens that cause
significant morbidity and mortality worldwide. However, no directed antiviral strategies are approved for use, in
part due to our limited understanding of fundamental aspects of their biology. Therefore, the objective of this
application is to investigate the role of capsid dynamics in virus biology using murine norovirus (MNV) as a
highly tractable model for studies of norovirus biology. Recent studies from us and others have identified key
modes of flexibility in the human and murine norovirus capsid that highlight their dynamic nature. Unlike any
other virus structure to date, the norovirus capsid exists in two states outside the cell, an expanded
conformation where the protruding (P) domain is raised up off the shell (S) domain, and a contracted
conformation, where the P domain rests on top of the S domain. The transition between these two states is
mediated by environmental cues, including bile acids, a key constituent in the intestinal lumen, luminal pH and
kosmotropic ions, like Ca2+. Multiple antibodies against human norovirus bind to epitopes accessible only in the
expanded conformation, while receptor binding occupancy is increased in the contracted conformation. A
second layer of flexibility lies within the P domain, in external loops that contain epitopes for neutralizing
antibodies. Escape from antibody neutralization and bile acid binding to the capsid influence the positioning of
these loops. Published and preliminary findings suggest a model whereby the expanded conformation
interfaces with the immune system, while the contracted form is optimized for cell/virus interactions. To
investigate this hypothesis, we will pursue the following aims in vitro and in vivo: 1) Determine the importance
of the flexible linker between P and S domain mediating contraction of the norovirus capsid on infectivity, and
2) Determine the importance of capsid protein loop flexibility on MNV infectivity. Towards that end, we will test
viral mutants with varying levels of flexibility by changing the linker length, and viral mutants lacking the bile
acid binding site. These conceptually innovative studies promise to be of high impact, because they will define
fundamental features of norovirus capsid dynamics and their role in infection and pathogenesis. Such
information is important for norovirus vaccine design.

## Key facts

- **NIH application ID:** 10225058
- **Project number:** 1R21AI154647-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Christiane Wobus
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $209,535
- **Award type:** 1
- **Project period:** 2021-03-05 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225058

## Citation

> US National Institutes of Health, RePORTER application 10225058, The role of norovirus capsid flexibility in infection and pathogenesis (1R21AI154647-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10225058. Licensed CC0.

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