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：
10624395
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/10624395
关键词：
Acceleration Acute Adult Animal Model Attenuated B-Lymphocytes Biological Assay Biological Models Biology Cells Childhood Data Dendritic Cells Diarrhea Disease Ensure Enteral Epithelial Cells Epithelium Event Feces Gastroenteritis Gastrointestinal Diseases Genetic Genetic Determinism Genetic Transcription Human Immune Immune Targeting Immunocompetent Immunologics Infection Intestinal Diseases Intestines Laboratory mice Lymphocyte Macrophage Maps Modeling Mus Neonatal Norovirus Oral Outcome Pathogenesis Pathogenicity Pathologic Peyer&apos s Patches Predisposition Primary Infection Process RNA Research Resistance 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 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.

项目概要诺如病毒是急性胃肠炎的主要原因，也是严重儿童期的主要原因 2003 年，我们发现了鼠诺如病毒 (MNV)，加速了防治全球性腹泻的进程。通过提供小动物模型并进一步了解发病机制然而，该模型系统的一个主要限制是野生型实验室。与人类相比，小鼠在感染 MNV 后并未出现明显的疾病诺如病毒在免疫功能正常的宿主中出现症状，这限制了该领域的能力。然而，应该指出的是，所有这些都阐明了诺如病毒诱发的疾病事件。迄今为止，MNV 的毒力研究均使用成年小鼠进行。诺如病毒感染在年轻宿主中更为严重，我们认为年轻小鼠会我们已经获得了令人兴奋的数据，证实了口腔疾病。 MNV 感染导致新生幼犬急性自愈性腹泻，这是一项变革性的发现对于诺如病毒领域，胃肠道疾病的严重程度受病毒遗传决定因素的调节。并与肠上皮的病理变化相关，尽管主要目标我们建议使用这个新系统来测试我们的工作。肠道免疫细胞的感染导致上皮细胞破坏的模型随后的腹泻。我们的主要目标是阐明腹泻的病毒决定因素，确定感染的关键免疫细胞靶点，并探究病毒与免疫细胞的相互作用这些目标的整合将使我们能够绘制关键病毒宿主图谱。相互作用导致肠道疾病。