Enterovirus Infection of Polarized Intestinal Cells

项目摘要/摘要： 这项应用的首要目标是确定肠道病毒感染人类的新机制。 肠上皮细胞。与肠道病毒感染人类肠道上皮有关的事件仍然存在 这在很大程度上是未知的，主要是因为缺乏合适的体内模型来概括肠道感染途径 在免疫活性环境中，以及标准培养细胞不能概括多细胞的性质 胃肠道上皮细胞。使用两个平行的人体肠上皮三维(3D)细胞模型 我们实验室最近开发的，包括一个基于干细胞的初级模型，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 将对(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的见解 肠道上皮；(2)肠道病毒感染对肠道上皮结构和功能的影响；以及 (3)上皮宿主干扰素信号在肠道病毒感染控制中的作用。这些目标是有前提的。 关于肠道细胞相关途径直接影响肠道病毒致病的中心假说 人体胃肠道。我们的建议开创了对多个方面的分子机制的研究。 肠道病毒与胃肠道细胞的相互作用。值得注意的是，我们的研究还将阐明病毒特定的致病途径， 这可能解释了为什么一些肠道病毒耐受性相对较好，而另一些则会导致严重的疾病。vt.给出 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广泛的专业知识，我们是独一无二的 进行这些研究，这将为我们对肠道病毒的理解提供新的范式 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.