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Elucidation of Pathogenic Mechanisms underlying Norovirus Diarrhea

阐明诺如病毒腹泻的致病机制

基本信息

批准号：
10413248
负责人：
Stephanie M Karst
金额：
$ 60.4万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10413248
关键词：
Acute Adult Animal Model Attenuated B-Lymphocytes Biological Assay Biological Models Biology Cells Childhood Data Dendritic Cells Diarrhea Disease Ensure Enteral Epithelial Epithelial Cells Event Feces Gastroenteritis Gastrointestinal Diseases Genetic Genetic Determinism Genetic Transcription Human Immune Immune Targeting Immunocompetent Immunologics Infection Intestinal Diseases Intestines Laboratory mice Lymphocyte Maps Modeling Mus Neonatal Norovirus Oral Outcome Pathogenesis Pathogenicity Pathologic Peyer&apos s Patches Primary Infection Process RNA Research Rotavirus Infections Severity of illness Small Intestines Symptoms System T-Lymphocyte Testing Tissues Tropism Viral Viral Proteins Virulence Virulence Factors Virulent Virus Virus Replication Work acute infection cell type cellular targeting diarrheal disease enteric infection gastrointestinal epithelium innovation insight interdisciplinary approach intestinal epithelium macrophage mouse model neonatal infection neonatal mice neonate neutrophil novel pup secondary lymphoid organ virus genetics virus host interaction

项目摘要

Project Summary Noroviruses are a major cause of acute gastroenteritis and the leading cause of severe childhood diarrhea globally. Our discovery of murine norovirus (MNV) in 2003 accelerated progress in the field by providing a small animal model and enabling further understanding of the pathogenesis of these enteric viruses. Yet a major limitation of this model system is that wild-type laboratory mice have not been shown to develop overt disease when infected with MNV, in contrast to human norovirus which is symptomatic in immunocompetent hosts. This limits the field’s ability to elucidate norovirus-induced events responsible for disease. It should be noted, however, that all virulence studies of MNV performed to date have used adult mice. Considering that human norovirus infections are more severe in younger hosts, we hypothesized that young mice would likewise be susceptible to MNV disease. We have generated exciting data confirming that oral MNV infection causes acute self-resolving diarrhea in neonatal pups, a transformative discovery for the norovirus field. Gastrointestinal disease severity is regulated by viral genetic determinants and is associated with pathological changes to the intestinal epithelium although the main targets of infection are intestinal immune cells. We propose to use this novel system to test our working model that infection of intestinal immune cells leads to disruption of the epithelium and consequent diarrhea. Our main objectives are to elucidate the viral determinants of diarrhea, define the key immune cell targets of infection, and probe the interactions of the virus with the intestinal epithelium. The integration of these aims will enable us to map key virus-host interactions responsible for intestinal disease.

项目总结