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

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

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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.

项目摘要/摘要诺如病毒是世界各地严重童年腹泻的主要原因，也是急性的主要原因所有年龄段的胃肠炎。目前没有批准的疫苗或针对诺如病毒的靶向疗法关于胃炎症状的病原机制的感染和知之甚少。获得多年来，对这种重要病毒的进一步了解已被用作模型系统并在理解诺如病毒生物学方面取得了重大进展。但是，没有症状感染鼠诺如病毒感染的免疫能力的成年小鼠限制了该模型的适用性疾病病毒机制。我们最近发现，基因野生型新生儿小鼠急性，自我分辨腹泻感染鼠诺诺未病毒，这是一种反映人类诺如病毒的疾病病程感染。这种新型的诺如病毒病的小动物模型代表了诺如病毒领域的重大进展由于它将能够完全表征病毒疾病机制，并最终充当平台测试体内抗病毒化合物的功效。使用此模型，我们观察到鼠北洛氏病毒感染肠中上皮下皮细胞，而不是肠上皮细胞。所在的机制诺如病毒在有症状感染期间转化上皮屏障，以达到其免疫细胞靶标是未知的，是我建议的特定目标1的重点。具体而言，我将检验以下假设诺如病毒使用两条公认的途径，用于大分子横跨肠上皮的大分子转运，微膜细胞和CX3CR1+抗原呈现的细胞，这些细胞表达跨石树突。虽然我们做到了在肠上皮细胞中未观察到病毒复制，在这些细胞的峰值中有丰富的病毒腹泻。鉴于这些细胞没有表达病毒受体，因此这一发现令人惊讶病毒复制。在我的提案的特定目的2中，我将检验以下假设：后代病毒与胆汁酸是通过肠上皮细胞内吞作用的转运蛋白。总体而言，我的研究重点是理解诺如病毒与肠上皮相互作用因为这些无疑是诱导腹泻的关键。