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.

项目摘要北病毒是急性胃肠炎的主要原因，也是严重童年的主要原因全球腹泻。我们在2003年发现诺如病毒（MNV）的发现，加速了通过提供小型动物模型并能够进一步了解发病机理这些肠道病毒。然而，该模型系统的主要限制是野生型实验室与人类相比诺如病毒在免疫能力宿主中是有症状的。这限制了该领域的能力阐明诺如病毒引起的疾病事件。但是，应该指出的是迄今为止对MNV进行的病毒研究使用了成年小鼠。考虑到那个人诺如病毒感染在年轻宿主中更为严重，我们假设年轻小鼠会同样容易受到MNV疾病的影响。我们生成了令人兴奋的数据，确认了口头 MNV感染引起新生儿幼犬的急性自我分解腹泻，这是一种变化的发现胃肠道疾病的严重程度受病毒遗传确定剂的调节并且与肠上皮的病理变化有关，尽管主要靶标感染的是肠道免疫细胞。我们建议使用这个新颖的系统测试我们的工作模型感染肠道免疫细胞会导致上皮中断和我们的主要目标是阐明腹泻的病毒决定剂，定义感染的关键免疫细胞靶标，并探测病毒与肠上皮。这些目标的整合将使我们能够绘制关键病毒宿主负责肠道疾病的相互作用。