The Role of FcRn in Echovirus Entry and Pathogenesis

项目摘要/摘要： 这项应用的首要目标是确定新生儿Fc受体(FcRN)在ECHO病毒中的作用 进入和发病机制。我们最近发现FcRN是一种泛ECHO病毒受体。我们证明了基因编辑 FcRN的表达减少了细胞对ECHO病毒的感染，反过来，异位表达促进了感染 在不允许的牢房里。我们还发现FcRN直接结合到回声病毒颗粒和增强的病毒上 附着在细胞上。与这些发现一致的是，重组FcRN蛋白或抗FcRN的单抗 阻断了多种细胞类型的埃科病毒感染。最后，对FcRN的人类同源物进行了表达 新生小鼠允许通过肠道途径感染E11，并显示出人类的表达，但 不是小鼠，FcRN的同源物恢复了非允许细胞类型中的ECHO病毒感染。然而，准确的 FcRN在Echo病毒入侵中的作用以及FcRN对Echo病毒致病机制的影响没有得到充分的分析 探索过了。本申请中提出的研究将为以下方面提供重要的见解：(1)FcRN在 ECHO病毒在肠上皮中的进入和运输，(2)FcRN在细胞类型特异性中的作用 (3)FcRN在ECHO病毒发病机制中的作用。我们的提案是先行者 从多个方面研究艾柯病毒感染的分子机制。重要的是，我们的 人和小鼠原代干细胞来源的肠上皮细胞模型的建立 基于细胞的肝脏模型和ECHO病毒致病的新体内模型都是高度创新的技术 这些进展将使我们能够直接评估ECHO病毒进入的许多方面的机制基础 以及生理相关模型中的发病机制。鉴于我们在肠道病毒研究方面的广泛专业知识，我们 都处于进行这些研究的独特地位，这将为我们对 回声病毒感染。

PROJECT SUMMARY/ABSTRACT: The overarching goal of this application is to identify the role of the neonatal Fc receptor (FcRn) in echovirus entry and pathogenesis. We recently identified FcRn as a pan-echovirus receptor. We showed that gene editing of FcRn resulted in reduced echovirus infection of cells, and reciprocally, ectopic expression promoted infection in non-permissive cells. We also found that FcRn bound directly to echoviral particles and enhanced virus attachment to cells. Consistent with these findings, recombinant FcRn protein or monoclonal antibodies to FcRn blocked echovirus infection in multiple cell types. Finally, expression of the human homologue of FcRn rendered neonatal mice permissive to E11 infection by the enteral route and showed that expression of the human, but not mouse, homologue of FcRn restored echovirus infection in non-permissive cell types. However, the precise role of FcRn in echovirus entry and a full analysis of the impact of FcRn on echovirus pathogenesis was not explored. The studies proposed in this application will provide important insights into (1) the role of FcRn in echovirus entry and trafficking in the intestinal epithelium, (2) the role of FcRn in the cell-type specific nature of echovirus infections in the liver, and (3) the role of FcRn in echovirus pathogenesis. Our proposal pioneers research into a variety of aspects of the molecular mechanisms of echovirus infections. Importantly, our development of primary human and mouse stem cell-derived models of the intestinal epithelium, in vitro primary cell-based liver models, and novel in vivo models of echovirus pathogenesis are highly innovative technical advances that will allow us to directly assess the mechanistic basis for a number of aspects of echovirus entry and pathogenesis in physiologically-relevant models. Given our extensive expertise in enterovirus research, we are uniquely positioned to perform these studies, which will provide new paradigms for our understanding of echovirus infections.