Interaction of Sindbis Virus with Cellular Processes

辛德比斯病毒与细胞过程的相互作用

• 批准号: 7828018
• 负责人: ILYA V. FROLOV
• 金额: $ 36.26万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7828018
• 关键词: Africa; Alphavirus; Animals; Antarctic Regions; Antiviral Agents; Capsid Proteins; Cell Communication; Cell physiology; Cells; Cellular Membrane; Cellular Stress; Cellular biology; Chikungunya virus; Complex; Cytoplasmic Granules; Cytoskeleton; Data; Development; Disease; Disease Outbreaks; Double-Stranded RNA; Elements; Encephalitis; Encephalitis Viruses; Endocytosis; Endosomes; Environment; Equine Encephalomyelitis; Family; Genome; Goals; Grant; Growth; Human; Immunologic Deficiency Syndromes; India; Island; Italy; Lead; Membrane; Modification; Molecular; Neurologic; Nonstructural Protein; Organelles; Polyproteins; Proteins; Public Health; RNA; RNA chemical synthesis; RNA replication; Research; Risk; Role; Sindbis Virus; Stress; Structure; Therapeutic; Time; Togaviridae; Viral; Viral Proteins; Virus; Virus Diseases; Virus Replication; base; forest; human disease; mutant; pathogen; promoter; protein complex; public health relevance; response; viral RNA

DESCRIPTION (provided by applicant): The Alphavirus genus in the Togaviridae family contains a number of significant human and animal pathogens that are widely distributed on all continents, excluding the Antarctic regions. Some of the alphaviruses, e.g., the Venezuelan (VEEV), eastern (EEEV) and western (WEEV) equine encephalitis viruses, cause severe human disease. Others, such as Sindbis (SINV) and Semliki Forest (SFV) viruses, are less pathogenic for humans, however, they employ similar replication strategy and are used for studying fundamental issues of the viral RNA synthesis. In the previous grant period, we made a number of important findings toward understanding the SINV genome replication that include i) uncovering the structure and functioning of the RNA promoter elements; ii) demonstration of the critical roles of the Old World alphavirus-specific nsP2 and the New World-specific capsid protein in virus-host cell interactions, in the development of transcriptional shutoff and cytopathic effect in the cells of vertebrate origin, and iii) identification of the viral and cellular components of the SINV-specific protein complexes. Most importantly, our recent studies demonstrated that SINV replication in the cells of vertebrate origin leads to formation of two types of nsP3-containing protein complexes. Based on our data, we hypothesize that the first type of nsP3-specific complexes is initially formed on the cellular membrane and, following endocytosis, remains associated with endosome-like, membrane-containing organelles. These complexes serve as replication complexes (RCs) in virus-specific RNA synthesis. The second type of complexes is associated with the cytoskeleton and has similar viral, but different cellular components, which are normally detected in cellular stress granules (SGs). The latter complexes either function as competitors for SG formation and/or serve in the preferential synthesis of viral proteins. The proposed research plan is focused on two broad Specific Aims: i) to study virus-specific protein complexes formation during SINV replication, and ii) to analyze functioning of cellular and viral proteins in SINV replication. PUBLIC HEALTH RELEVANCE: Alphaviruses comprise a group of widely distributed human and animal pathogens; some of them induce highly debilitating diseases and represent a serious public health threat in the US. The goal of this proposal is to understand the role of the cellular environment in viral infection. Identification of the cellular proteins that are essential for virus growth will lead to development of new antiviral therapeutic strategies.

描述（由申请人提供）：Togaviridae家族中的α病毒属包含许多重要的人类和动物病原体，这些病原体广泛分布在所有大陆上，不包括南极地区。一些α病毒，例如委内瑞拉（VEEV），东部（EEEV）和西部（Weev）马脑炎病毒，引起严重的人类疾病。但是，其他人，例如sindbis（Sinv）和Semliki Forest（SFV）病毒，对人类的致病性较低，但是，它们采用了类似的复制策略，用于研究病毒RNA合成的基本问题。在上一个赠款期间，我们为理解包括i）揭示RNA启动子元素的结构和功能的SINV基因组复制做出了许多重要发现； ii）演示了旧世界α-病毒特异性NSP2的关键作用以及新的世界特异性衣壳蛋白在病毒宿主相互作用中的关键作用，在脊椎动物起源细胞中转录关闭和胞质变性效应的开发中，以及III的III）鉴定了病毒和细胞组成部分的病毒和细胞成分。最重要的是，我们最近的研究表明，脊椎动物起源细胞中的SINV复制导致形成两种含NSP3的蛋白质复合物。基于我们的数据，我们假设第一类NSP3特异性复合物最初是在细胞膜上形成的，并且在内吞作用后仍与内体样，含膜的细胞器保持相关。这些复合物是病毒特异性RNA合成中的复制复合物（RC）。第二种复合物与细胞骨架有关，具有相似的病毒，但具有不同的细胞成分，这些细胞成分通常在细胞应激颗粒（SGS）中检测到。后者的复合物可以作为SG形成的竞争者和/或服务于病毒蛋白的优先合成。拟议的研究计划集中在两个广泛的特定目的上：i）在SINV复制过程中研究病毒特异性蛋白复合物的形成，ii）分析在SINV复制中细胞和病毒蛋白的功能。公共卫生相关性：α病毒包括一组广泛分布的人类和动物病原体；他们中的一些人引起了高度令人衰弱的疾病，并代表了美国的严重公共卫生威胁。该提案的目的是了解细胞环境在病毒感染中的作用。对病毒生长必不可少的细胞蛋白的鉴定将导致新的抗病毒治疗策略的发展。