权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Cell Biology of Enterovirus Infection in Polarized Epithelial Cells

极化上皮细胞肠道病毒感染的细胞生物学

基本信息

批准号：
7493874
负责人：
JEFFREY M. BERGELSON
金额：
$ 40.47万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-15 至 2008-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7493874
关键词：
Actins Apical Architecture Binding Biological CD55 Antigens Capsid Caveolae Cell membrane Cell physiology Cells Cellular biology Coxsackie B Viruses Coxsackie Viruses Cytoskeleton DNA Sequence Rearrangement Data Depth Drug Delivery Systems Echo Viruses Echovirus 6 Echovirus Infections Endoplasmic Reticulum Enterovirus Enterovirus Infections Epithelial Cells Epithelium Event Guanosine Triphosphate Phosphohydrolases Human Infection Intervention Intestinal Mucosa Intestines Label Libraries Movement Myocarditis Numbers Oral Pathway interactions Penetration Pharmaceutical Preparations Phosphotransferases Process Role Route Signal Pathway Signal Transduction Signaling Molecule Simian B disease Site Small Interfering RNA Surface Tight Junctions Viral meningitis Virus adenovirus receptor basolateral membrane cellular microvillus gastrointestinal microvillus inhibitor/antagonist intestinal epithelium pathogen polarized cell prevent receptor research study response viral RNA

项目摘要

Summary: Enteroviruses are transmitted by the fecal-oral route, and must cross the intestinal mucosa to initiate infection. The intestines are lined by polarized epithelial cells, with distinct apical and basolateral surfaces; intercellular tight junctions prevent virus access to receptors on basolateral membranes. Many enteroviruses, including many coxsackie B viruses (CBV) and echoviruses (EV), appear to have evolved independently to bind to decay accelerating factor (DAF), a molecule expressed on the surface of polarized epithelium. We believe that these viruses use DAF to interact with epithelial cells in the intestinal lumen DAF does more than simply provide a site for virus attachment. We recently found that it initiates at least two intracellular signaling pathways required for CBV entry and infection in polarized cells: activation of Abl kinase leads to actin rearangements and virus movement to the tight junction, where interaction with the coxsackievirus and adenovirus receptor (CAR) initiates the uncoating process that releases viral RNA; activation of Fyn kinase triggers virus internalization in caveolae, and delivery to the endoplasmic reticulum (ER) where uncoating is completed before replication ensues. These results suggest that infection of polarized cells is likely to involve distinctive cell biological mechanisms. We propose three sets of experiments to examine the cell biology of infection in polarized epithelium. 1. We will define the pathway by which DAF-binding EV enter polarized epithelium, following the entry of labeled virus, and using specific inhibitors (drugs, siRNAs) to dissect the underlying cellular processes. 2. We will determine the function of actin rearrangements and changes in microvillus architecture during virus entry, and identify the mechanism by which actin reorganization is initiated in response to virus- DAF interaction. 3. We will screen an siRNA library to identify signaling molecules required for CBV entry into polarized epithelium, and define the role of specific signaling molecules in the process of infection. Relevance: Enteroviruses are the major cause of viral meningitis, and the second major cause of myocarditis in the US, and interaction with polarized epithelium is the first step in infection. Understanding the special mechanisms by which they infect polarized cells will reveal new potential drug targets.

摘要：肠道病毒通过粪-口途径传播，必须穿过肠粘膜，引发感染。肠由极化的上皮细胞排列，具有明显的顶侧和底侧表面;细胞间紧密连接阻止病毒进入基底外侧膜上的受体。许多肠道病毒，包括许多科萨基B病毒（CBV）和埃可病毒（EV），似乎已经进化独立地与衰变加速因子（decay accelerating factor，简写为ERF）结合，ERF是一种表达在极化细胞表面的分子，上皮我们认为这些病毒利用E2与肠腔中的上皮细胞相互作用防毒墙不仅仅是提供一个病毒附着的场所。我们最近发现， CBV进入和感染极化细胞所需的至少两种细胞内信号传导途径： Abl激酶导致肌动蛋白重排和病毒移动到紧密连接处，在紧密连接处，柯萨奇病毒和腺病毒受体（CAR）启动释放病毒RNA的脱包被过程; Fyn激酶的激活触发病毒在小窝中的内化，并递送至内质网 (ER)其中在复制包封之前完成去涂层。这些结果表明，极化细胞可能涉及独特的细胞生物学机制。我们建议三套在极化上皮中检查感染的细胞生物学的实验。 1.我们将确定DAF结合EV进入极化上皮的途径，标记的病毒，并使用特定的抑制剂（药物，siRNA）来剖析潜在的细胞过程。 2.我们将确定肌动蛋白重排的功能和微绒毛结构的变化在病毒进入过程中，并确定肌动蛋白重组启动的机制，以响应病毒- DAF互动。 3.我们将筛选siRNA文库以鉴定CBV进入极化细胞所需的信号分子，上皮细胞，并确定特定的信号分子在感染过程中的作用。相关性：肠道病毒是病毒性脑膜炎的主要原因，心肌炎在美国，和极化上皮细胞的相互作用是感染的第一步。理解它们感染极化细胞的特殊机制将揭示新的潜在药物靶点。