Characterizing the Role of Specific Host Lipids during Reovirus Cell Entry

项目摘要/摘要 病毒与宿主的相互作用在病毒生命周期的许多阶段发挥着重要作用，包括进入细胞。 了解促进病毒进入的机制对于开发有效的治疗方法是必要的 防止被重要的人类病原体感染。哺乳动物正病毒(呼肠孤病毒)，一种久负盛名的 研究无包膜病毒入侵机制的模型系统经历了一系列调节 结构转变最终导致宿主膜的穿透和病毒遗传物质的传递。 其中一种构象变化，传染性亚病毒颗粒(ISVP)到ISVP*的转换，是由 MYR-µ1N，一种在病毒进入过程中从病毒颗粒中释放出来的肉豆蔻酰化肽。此外，特定的脂类 优化MYR-µ1N的ISVP*推广活动。因此，呼肠孤病毒和脂质之间的相互作用揭示了一种 截然不同的病毒-宿主相互作用，在这种相互作用中，膜可以积极地参与一种 无包膜病毒。本提案中概述的两个具体目标采用了多学科方法。 探讨调节脂质促进呼肠孤病毒进入的分子机制。在具体目标1中， 生化和成像技术将被用来定义构成脂质基础的生物物理性质- 介导的ISVP到ISVP*的转化和膜穿透。在具体目标2中，基因技术将是 用于确定脂质相关MYR-µ1N中必要的引发感染的特定残留物。 这项拟议的研究将为无包膜病毒的策略提供重要的知识 用于与宿主细胞相互作用，以及这些相互作用如何有助于建立生产性感染。

Project Summary/Abstract Virus-host interactions play an essential role in many stages of the viral lifecycle, including cell entry. Understanding the mechanisms that facilitate virus entry is necessary for developing effective therapies that prevent infection by important human pathogens. Mammalian orthoreovirus (reovirus), a well-established model system for studying the entry mechanisms of nonenveloped viruses, undergoes a series of regulated structural transitions that culminate in penetration of host membranes and delivery of the viral genetic material. One of these conformational changes, infectious subviral particle (ISVP)-to-ISVP* conversion, is promoted by myr-µ1N, a myristoylated peptide that is released from the virus particle during entry. Moreover, specific lipids optimize the ISVP* promoting activity of myr-µ1N. Thus, the interplay between reovirus and lipids reveals a distinct virus-host interaction in which membranes can actively participate in the entry process of a nonenveloped virus. The two specific aims that are outlined in this proposal utilize a multidisciplinary approach to investigate the molecular mechanisms that regulate lipid-facilitated reovirus entry. In Specific Aim 1, biochemical and imaging techniques will be used to define the biophysical properties that underlie lipid- mediated ISVP-to-ISVP* conversion and membrane penetration. In Specific Aim 2, genetic techniques will be used to identify the specific residues within lipid-associated myr-µ1N that are necessary initiating infection. The proposed research will contribute significant knowledge to the strategies that nonenveloped viruses can use to interact with host cells and how these interactions aid in the establishment of a productive infection.