Enterovirus Infection of Polarized Intestinal Cells

极化肠细胞的肠道病毒感染

基本信息

批准号：
10451694
负责人：
Carolyn B Coyne
金额：
$ 39.47万
依托单位：
DUKE UNIVERSITY
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：
2021-07-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10451694
关键词：
3-Dimensional Apoptotic Cell Communication Cell Line Cell model Cells Cellular Structures Complex Coxsackie B Viruses Coxsackie Viruses Cues Cultured Cells Data Disease Echo Viruses Enteral Enterovirus Enterovirus 68 Enterovirus 71 Enterovirus Infections Environment Epithelial Epithelial Cells Event Functional disorder Gastrointestinal tract structure Gene Expression Profile Goals Growth Human Human poliovirus Immune response Immune signaling Immunocompetent Immunologics In Vitro Infection Inflammatory Interferon-beta Interferons Intestines Laboratories Lead Life Cycle Stages Modeling Molecular Mus Nature Nonlytic Oral Organ Pathogenesis Pathogenicity Pathway interactions Persons Physiological Positioning Attribute Property Research Role Route Signal Transduction Specificity Structure Surface System Testing Tissues Viral Virus base cell type exosome extracellular gastrointestinal gastrointestinal epithelium human model in vitro Model in vivo in vivo Model insight intestinal crypt intestinal epithelium intestinal homeostasis microbial mouse model new therapeutic target novel particle prevent response self-renewal stem cell differentiation stem cell model stem cells therapeutically effective

项目摘要

PROJECT SUMMARY/ABSTRACT: The overarching goal of this application is to identify novel mechanisms by which enteroviruses infect the human intestinal epithelium. The events associated with enterovirus infections of the human intestinal epithelium remain largely unknown, largely due to the lack of suitable in vivo models that recapitulate the enteral route of infection in an immunocompetent setting and the inability of standard cultured cells to recapitulate the multicellular nature of the GI epithelium. Using two parallel three-dimensional (3-D) cell models of the human intestinal epithelium recently developed in our laboratory, including a primary stem cell-based model, we have identified several unique mechanisms used by enteroviruses to infect the GI epithelium. The studies proposed in this application will provide important insights into (1) the role of non-lytic release in the enterovirus life cycle in the human intestinal epithelium, (2) the impact of enterovirus infections on intestinal epithelial structure and function, and (3) the role of epithelial host interferon signaling in the control of enteroviral infections. These goals are premised on the central hypothesis that intestinal cell-associated pathways directly impact enterovirus pathogenesis in the human GI tract. Our proposal pioneers research into a variety of aspects of the molecular mechanisms of enterovirus-GI cell interactions. Notably, our research will also illuminate virus specific-pathogenic pathways, which may explain why some enteroviruses are relatively well-tolerated, and others cause severe disease. Given our extensive expertise in enterovirus research, specifically studies related to the GI tract, we are uniquely positioned to perform these studies, which will provide new paradigms for our understanding of enterovirus infections of the GI epithelium.

项目概要/摘要：该应用的总体目标是确定肠道病毒感染人类的新机制肠上皮。与人类肠上皮肠道病毒感染相关的事件仍然存在很大程度上未知，很大程度上是由于缺乏合适的体内模型来概括肠道感染途径在免疫功能正常的环境中，标准培养细胞无法重现多细胞性质胃肠道上皮。使用两个平行的人体肠上皮三维 (3-D) 细胞模型最近在我们的实验室开发，包括基于原代干细胞的模型，我们已经确定了几个肠道病毒利用独特的机制感染胃肠道上皮。本申请中提出的研究将为（1）非裂解释放在人类肠道病毒生命周期中的作用提供重要见解肠上皮，（2）肠道病毒感染对肠上皮结构和功能的影响，以及 (3)上皮宿主干扰素信号传导在控制肠道病毒感染中的作用。这些目标是有前提的核心假设是肠道细胞相关途径直接影响肠道病毒的发病机制人类胃肠道。我们的建议开创了对分子机制各个方面的研究肠道病毒-胃肠道细胞相互作用。值得注意的是，我们的研究还将阐明病毒特定的致病途径，这可以解释为什么一些肠道病毒的耐受性相对良好，而另一些则会引起严重的疾病。给定我们在肠道病毒研究，特别是与胃肠道相关的研究方面拥有丰富的专业知识，我们是独一无二的定位于进行这些研究，这将为我们理解肠道病毒提供新的范式胃肠道上皮感染。