# Using a novel neonatal mouse model to determine mechanisms of norovirus-induced disease

> **NIH NIH F30** · UNIVERSITY OF FLORIDA · 2022 · $43,081

## Abstract

Project Summary/Abstract
Norovirus is the leading cause of severe childhood diarrhea around the world and a major cause of acute
gastroenteritis in all age groups. There are no currently approved vaccines or targeted therapeutics for norovirus
infection and very little is known about the pathogenic mechanisms underlying gastroenteritis symptoms. To gain
further understanding of this important virus, murine norovirus has been used as a model system for many years
and has led to many significant advances in understanding norovirus biology. However, the absence of
symptoms in immunocompetent adult mice infected with murine norovirus limits the applicability of this model to
delineation of viral mechanisms of disease. We recently discovered that genetically wild-type neonatal mice
develop acute, self-resolving diarrhea when infected with murine norovirus, a disease course that mirrors human
norovirus infection. This novel small animal model of norovirus disease represents a major advance in the
norovirus field since it will enable a complete characterization of viral disease mechanisms and ultimately serve
as a platform to test the efficacy of antiviral compounds in vivo. While developing this new model, we observed
differences in disease severity between genetically similar murine norovirus strains enabling identification of viral
determinants of norovirus-induced disease. The objectives of this proposal are to elucidate the cellular
tropism and pathogenic mechanisms underlying norovirus diarrhea using our novel symptomatic small
animal model. In Specific Aim 1, I will test the hypothesis that infection of lymphocytes is critical to norovirus-
induced diarrhea. This hypothesis is strongly supported by our in vitro findings revealing that, although virulent
and attenuated strains replicate comparably in macrophages, only the virulent strain replicates in lymphocytes.
Moreover, mutations abolishing lymphocyte infection in vitro are attenuating in adult interferon-deficient mice. In
Specific Aim 2, I will test the hypothesis that virus-induced proinflammatory cytokines cause disruptions in tight
junctions maintaining the intestinal epithelial barrier, consequently leading to increased intestinal permeability
and diarrhea. This hypothesis is based on our observation that a virulent murine norovirus strain induces
significantly more proinflammatory cytokine expression than attenuated strains despite comparable levels of viral
replication; and on the well-established ability of proinflammatory cytokines to disrupt tight junctions. Overall, the
studies described in this proposal will test our model that norovirus infection of intestinal immune cells induces
a host response that is immunopathologic and leads to diarrhea via effects on the intestinal epithelial barrier.

## Key facts

- **NIH application ID:** 10451637
- **Project number:** 5F30AI154834-03
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Emily Winesett Helm
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $43,081
- **Award type:** 5
- **Project period:** 2020-08-16 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10451637

## Citation

> US National Institutes of Health, RePORTER application 10451637, Using a novel neonatal mouse model to determine mechanisms of norovirus-induced disease (5F30AI154834-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10451637. Licensed CC0.

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