The Role of FcRn in Echovirus Entry and Pathogenesis

FcRn 在埃可病毒进入和发病机制中的作用

基本信息

批准号：
10571945
负责人：
Carolyn B Coyne
金额：
$ 52.07万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10571945
关键词：
Acute Liver Failure Adult Aseptic Meningitis Biology Bypass Cells Cessation of life Dangerousness Data Development Disease Echo Viruses Echovirus 9 Echovirus Infections Ectopic Expression Encephalitis Endothelial Cells Enterocytes Enterovirus Epithelial Cells Exhibits Fc Receptor Genes Goals Hepatic Hepatitis Hepatocyte Homologous Gene Human In Vitro Individual Infant Infection Infectious Agent Integration Host Factors Intestines Kupffer Cells Liver Mediating Meningitis Modeling Molecular Monoclonal Antibodies Mus Nature Neonatal Neonatal Mortality Neurologic Pathogenesis Physiological Play Population Positioning Attribute Proteins Reagent Recombinants Research Role Route Sepsis Serotyping Site Specificity Subgroup Tissues Transgenic Organisms Tropism Viral Virus cell type defined contribution enteric infection experimental study human stem cells in vivo in vivo Model innovation insight intestinal epithelium liver infection monolayer mortality mouse model neonatal Fc receptor neonatal mice neonatal morbidity neonate nervous system disorder novel particle permissiveness prevent receptor receptor binding receptor expression receptor internalization stem cell model therapeutically effective tissue tropism trafficking transcytosis virus tropism

项目摘要

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.

项目概要/摘要：该应用的首要目标是确定新生儿 Fc 受体 (FcRn) 在埃可病毒中的作用进入和发病机制。我们最近发现 FcRn 是一种泛艾可病毒受体。我们证明了基因编辑 FcRn 的表达导致细胞埃可病毒感染减少，反之，异位表达促进感染在不允许的细胞中。我们还发现 FcRn 直接与埃可病毒颗粒结合并增强病毒附着于细胞。与这些发现一致，重组FcRn蛋白或FcRn单克隆抗体阻断多种细胞类型中的埃可病毒感染。最后，FcRn 的人类同源物的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 FcRn 同源物不是小鼠，而是在不允许的细胞类型中恢复了埃可病毒感染。然而，准确的 FcRn 在埃可病毒进入中的作用以及 FcRn 对埃可病毒发病机制影响的全面分析尚未完成探索过。本申请中提出的研究将为 (1) FcRn 在艾可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肝脏中的埃可病毒感染，以及（3）FcRn 在埃可病毒发病机制中的作用。我们的提案先驱对埃可病毒感染分子机制的各个方面进行研究。重要的是，我们的开发原代人类和小鼠干细胞衍生的肠上皮模型，体外原代基于细胞的肝脏模型和埃可病毒发病机制的新型体内模型是高度创新的技术这些进展将使我们能够直接评估埃可病毒进入许多方面的机制基础和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丰富专业知识，我们具有独特的优势来进行这些研究，这将为我们的理解提供新的范式艾可病毒感染。