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Tegument ICP0 and HSV Entry

皮层 ICP0 和 HSV 条目

基本信息

批准号：
8244712
负责人：
ANTHONY V NICOLA
金额：
$ 8.33万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-19 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8244712
关键词：
Tegument ICP0 HSV Entry

项目摘要

DESCRIPTION (provided by applicant): Herpes simplex virus (HSV) is a common and significant human pathogen that causes lifelong latent infection and a variety of diseases, ranging from cold sores and genital lesions to blindness and fatal encephalitis. Proteins within the tegument layer of HSV are released into the cell upon entry when the viral envelope fuses with the cell membrane. HSV capsids and capsid-associated tegument proteins then utilize the host cytoskeletal machinery for transport to the nucleus. We recently showed that incoming HSV employs the 26S proteasome machinery at a postpenetration step to initiate infection. ICP0 is a multi-functional viral protein that is synthesized by the infected cell with immediate-early kinetics. ICP0 has a zinc binding RING finger motif that confers E3 ubiquitin ligase activity. ICP0 is also a component of the virion tegument and is brought into the cell with the infecting viral particle. The functional role of tegument ICP0 has been largely undetermined. Our preliminary studies indicate a role for ICP0 in proteasome-dependent viral entry. The long-term goal of this project is to understand the virus-cell interactions that HSV uses to gain access to the host cell nucleus during the earliest stages of infection. The objective of this proposal is to determine the fate and function of tegument ICP0 in the context of pre-immediate early events in HSV infection. Our central hypothesis is that tegument ICP0 modulates the proteasome-dependent delivery of the viral nucleocapsid from the cell periphery to the nucleus. Two aims are proposed. In Specific Aim 1, the precise step in the entry process that is affected by ICP0 will be defined. The role of the RING finger domain of ICP0 in the proteasome-dependent transport of capsids will also be analyzed. In Specific Aim 2, the stability and subcellular localization of tegument ICP0 will be determined. The roles of the proteasome and of ICP0 functional domains in these processes will be defined. A combination of molecular, biochemical and cell biological approaches will be used to achieve these goals. These studies will widen our understanding of the mechanism for capsid targeting to the nucleus to initiate productive infection. By identifying new requirements for virus entry into the host, the results will increase our knowledge of the early steps of HSV infection and reveal targets for novel therapeutic intervention. PUBLIC HEALTH RELEVANCE: Herpes simplex virus is a common cause of infections and can cause serious complications such as neonatal infections and fatal encephalitis. The purpose of this research is to determine how the herpes simplex virus initiates infection in humans by studying the virus interaction with host cells. Greater understanding of the virus entry process may help to develop novel approaches to prevent herpes infections.

描述（由申请人提供）：单纯疱疹病毒（HSV）是一种常见且重要的人类病原体，可导致终生潜伏感染和多种疾病，从唇疱疹和生殖器病变到失明和致命性脑炎。当病毒包膜与细胞膜融合时，HSV 皮层内的蛋白质在进入细胞后释放到细胞中。然后，HSV 衣壳和衣壳相关的外被蛋白利用宿主细胞骨架机制转运至细胞核。我们最近表明，传入的 HSV 在渗透后步骤中利用 26S 蛋白酶体机制来启动感染。 ICP0 是一种多功能病毒蛋白，由受感染细胞以立即早期动力学合成。 ICP0 具有锌结合环指基序，赋予 E3 泛素连接酶活性。 ICP0 也是病毒颗粒外皮的组成部分，并与感染病毒颗粒一起进入细胞。皮层 ICP0 的功能作用在很大程度上尚未确定。我们的初步研究表明 ICP0 在蛋白酶体依赖性病毒进入中发挥作用。该项目的长期目标是了解 HSV 在感染的最早阶段利用病毒与细胞的相互作用来进入宿主细胞核。该提案的目的是确定 HSV 感染前立即早期事件背景下皮层 ICP0 的命运和功能。我们的中心假设是，体被 ICP0 调节病毒核衣壳从细胞外周到细胞核的蛋白酶体依赖性递送。提出了两个目标。在具体目标 1 中，将定义受 ICP0 影响的进入流程中的精确步骤。 ICP0 的环指结构域在衣壳的蛋白酶体依赖性运输中的作用也将被分析。在具体目标 2 中，将确定外皮 ICP0 的稳定性和亚细胞定位。蛋白酶体和 ICP0 功能域在这些过程中的作用将被定义。将结合分子、生物化学和细胞生物学方法来实现这些目标。这些研究将加深我们对衣壳靶向细胞核以启动生产性感染的机制的理解。通过确定病毒进入宿主的新要求，研究结果将增加我们对 HSV 感染早期步骤的了解，并揭示新的治疗干预的目标。公共卫生相关性：单纯疱疹病毒是感染的常见原因，可引起严重的并发症，例如新生儿感染和致命性脑炎。本研究的目的是通过研究病毒与宿主细胞的相互作用来确定单纯疱疹病毒如何在人类中引发感染。对病毒进入过程的更多了解可能有助于开发预防疱疹感染的新方法。