Characterizing the Role of Specific Host Lipids during Reovirus Cell Entry

表征特定宿主脂质在呼肠孤病毒进入细胞过程中的作用

• 批准号: 9327232
• 负责人: ANTHONY J SNYDER
• 金额: $ 6.02万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9327232
• 关键词: Address; Affect; Affinity; Amino Acids; Area; Biochemical; Biochemistry; Biological Assay; Biological Models; Biophysics; Cathepsins; Cell Communication; Cell membrane; Cells; Cellular biology; Collaborations; Development; Disease; Distant; Double Stranded RNA Virus; Enterovirus; Environment; Event; Experimental Models; Fluorescence Microscopy; Foundations; Genetic; Genetic Materials; Genetic Techniques; Goals; Human; Imaging Techniques; In Vitro; Indiana; Individual; Infection; Infection prevention; Knowledge; Lipid Chemistry; Lipids; Mammalian Orthoreovirus; Mediating; Membrane; Mentors; Microbiology; Molecular; Molecular Conformation; Mutation; Pathway interactions; Penetration; Peptide Hydrolases; Peptides; Phylogenetic Analysis; Play; Process; Reaction; Recruitment Activity; Reoviridae; Reovirus; Research; Role; Rotavirus; Scientific Advances and Accomplishments; Scientist; Series; Techniques; Training; Universities; Viral; Virion; Virus; Virus Diseases; Virus Replication; Work; base; biophysical properties; effective therapy; graduate student; interdisciplinary approach; membrane model; novel strategies; particle; pathogen; undergraduate student; virology; virus envelope; virus genetics; virus host interaction

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.

项目总结/摘要 病毒-宿主相互作用在病毒生命周期的许多阶段中发挥重要作用，包括进入细胞。 了解促进病毒进入的机制对于开发有效的疗法是必要的， 预防重要的人类病原体感染。哺乳动物正呼肠孤病毒（呼肠孤病毒），一种成熟的 研究无包膜病毒进入机制的模型系统，经历了一系列的调节， 结构转变，最终穿透宿主细胞膜并传递病毒遗传物质。 这些构象变化之一，感染性亚病毒颗粒（ISVP）到ISVP * 的转化，是由 myr-µ 1 N，一种豆蔻酰化肽，在病毒颗粒进入时释放。此外，特定的脂质 优化myr-µ 1 N的ISVP* 促进活性。因此，呼肠孤病毒和脂质之间的相互作用揭示了 不同的病毒-宿主相互作用，其中膜可以积极参与进入过程， 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 研究调节脂质促进呼肠孤病毒进入的分子机制。具体目标1、 生物化学和成像技术将被用来确定生物物理特性，基础脂质， 介导的ISVP至ISVP* 转化和膜渗透。在具体目标2中，遗传技术将被 用于鉴定启动感染所必需的脂质相关myr-µ 1 N中的特定残基。 拟议的研究将为无包膜病毒可以 用于与宿主细胞相互作用以及这些相互作用如何帮助建立生产性感染。