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The Role of Norovirus Interactions with the Epithelial Barrier in Acute Gastroenteritis

诺如病毒与上皮屏障相互作用在急性胃肠炎中的作用

基本信息

批准号：
10679788
负责人：
Amy Marie Peiper
金额：
$ 4.19万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-16 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679788
关键词：
ASBT protein Acids Acute Adult Animal Model Antigen-Presenting Cells Antiviral Agents Antiviral Therapy Bile Acids Binding Biological Models Biology Biopsy Cells Cessation of life Childhood Complex Data Dendrites Detection Development Diarrhea Disease Enteral Enterohepatic Circulation Epithelial Cells Epithelium Fellowship Gastroenteritis Goals Health Human Immune Immune Targeting Immunocompetent Immunocompromised Host Infection Ingestion Intestinal Diseases Intestines Kinetics Lamina Propria Liver Mentors Modeling Movement Mus Norovirus Pathogenesis Pathogenicity Pattern Peyer&apos s Patches Physicians Population Preventive treatment Reporter Research Role Route Scientist Severity of illness Symptoms Testing Time Training Tropism Vaccines Villous Viral Virion Virus Virus Diseases Virus Receptors Virus Replication Work age group burden of illness career cellular targeting efficacy testing ileum improved in vivo intestinal epithelium intestinal villi mortality mouse model neonatal mice novel pathogen pup receptor targeted treatment therapeutic development transcytosis uptake virology

项目摘要

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 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. Using this model, we have observed that murine norovirus infects subepithelial immune cells in the intestine but not intestinal epithelial cells. The mechanisms by which murine norovirus transcytoses the epithelial barrier to reach its immune cell targets during symptomatic infection is unknown and is the focus on Specific Aim 1 of my proposal. Specifically, I will test the hypothesis that murine norovirus uses two well-established routes for macromolecular transport across the intestinal epithelium, microfold cells and CX3CR1+ antigen presenting cells that express transepithelial dendrites. Although we did not observe viral replication in intestinal epithelial cells, there was abundant virus in these cells at the peak of diarrhea. This finding was surprising given that these cells do not express the virus receptor, nor do they support viral replication. In Specific Aim 2 of my proposal, I will test the hypothesis that progeny virus complexed with bile acids are endocytosed by intestinal epithelial cells via engagement of the apical sodium-dependent bile acid transporter. Overall, my research focuses on understanding norovirus interactions with the intestinal epithelium because these are undoubtedly key to the induction of diarrhea.

项目总结/文摘