Enterovirus Infection of Polarized Intestinal Cells

项目总结/摘要： 本申请的首要目标是确定肠道病毒感染人类的新机制 肠上皮与肠道病毒感染人类肠上皮相关的事件仍然存在， 很大程度上是未知的，主要是由于缺乏合适的体内模型，重现肠内感染途径 在免疫活性环境中，标准培养细胞不能再现多细胞性质， 胃肠道上皮细胞使用两个平行的人肠上皮三维（3-D）细胞模型， 最近在我们的实验室开发，包括一个主要的干细胞为基础的模型，我们已经确定了几个 肠道病毒感染胃肠道上皮的独特机制。本申请中提出的研究 将提供重要的见解（1）在人类肠道病毒生命周期中的非裂解释放的作用， 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在控制肠道病毒感染中的作用。这些目标是明确的 关于肠细胞相关途径直接影响肠道病毒发病机制的中心假设， 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异性致病途径， 这可能解释了为什么有些肠道病毒相对耐受良好，而另一些则导致严重疾病。给定 我们在肠道病毒研究方面的广泛专业知识，特别是与胃肠道相关的研究，我们是独一无二的 这些研究将为我们了解肠道病毒提供新的范例 胃肠道上皮感染。

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.