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：
10409265
负责人：
Carolyn B Coyne
金额：
$ 40.25万
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/10409265
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 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.

项目摘要/摘要：该应用的总体目标是识别肠病毒感染人类的新型机制肠上皮。与人肠上皮的肠肠病毒感染相关的事件仍然存在在很大程度上未知，主要是由于缺乏概括肠内感染途径的体内模型在免疫能力的环境和标准培养的细胞无法概括多细胞性质的情况下胃肠地上皮。使用人类肠上皮的两个平行的三维（3-D）细胞模型最近在我们的实验室中开发的，包括基于干细胞的主要模型，我们已经确定了几个肠病毒用来感染胃肠道上皮的独特机制。该应用中提出的研究将为（1）非散散释放在人类肠病毒生命周期中的作用提供重要的见解肠上皮，（2）肠病毒感染对肠上皮结构和功能的影响（3）上皮宿主干扰素信号在控制肠病毒感染中的作用。这些目标是前提的关于肠细胞相关途径直接影响肠病毒发病机理的中心假设人胃肠道。我们提出的先驱者研究了分子机制的各个方面肠病毒GI细胞相互作用。值得注意的是，我们的研究还将照亮病毒特异性疾病的途径，这可以解释为什么某些肠病毒相对耐受性良好，而另一些则引起严重疾病。给出我们在肠病毒研究方面的广泛专业知识，特别是与胃肠道有关的研究，我们是独特的有能力进行这些研究，这将为我们理解肠病毒提供新的范式胃肠道上皮的感染。