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）：披膜病毒科的甲病毒属含有许多重要的人类和动物病原体，广泛分布于除南极地区外的所有大陆。一些甲病毒，例如委内瑞拉马脑炎病毒（VEEV）、东部马脑炎病毒（EEEV）和西部马脑炎病毒（WEEV），会引起严重的人类疾病。其他病毒，如 Sindbis (SINV) 和 Semliki Forest (SFV) 病毒对人类的致病性较低，但它们采用类似的复制策略，用于研究病毒 RNA 合成的基本问题。在上一个资助期间，我们在理解 SINV 基因组复制方面取得了许多重要发现，包括 i) 揭示了 RNA 启动子元件的结构和功能； ii) 证明旧世界甲病毒特异性 nsP2 和新世界特异性衣壳蛋白在病毒-宿主细胞相互作用、脊椎动物起源细胞转录关闭和细胞病变效应的发展中的关键作用，以及 iii) 鉴定SINV 特异性蛋白复合物的病毒和细胞成分。最重要的是，我们最近的研究表明，SINV 在脊椎动物来源的细胞中复制导致形成两种类型的含 nsP3 的蛋白质复合物。根据我们的数据，我们假设第一种类型的 nsP3 特异性复合物最初在细胞膜上形成，并在内吞作用后仍然与内体样含膜细胞器相关。这些复合物在病毒特异性 RNA 合成中充当复制复合物 (RC)。第二种类型的复合物与细胞骨架相关，具有相似的病毒但不同的细胞成分，通常在细胞应激颗粒（SG）中检测到。后者复合物或者作为 SG 形成的竞争者，和/或用于病毒蛋白的优先合成。拟议的研究计划侧重于两个广泛的具体目标：i）研究 SINV 复制过程中病毒特异性蛋白复合物的形成，ii）分析 SINV 复制过程中细胞和病毒蛋白的功能。公共卫生相关性：甲病毒由一组广泛分布的人类和动物病原体组成；其中一些会诱发高度衰弱的疾病，并对美国的公共健康构成严重威胁。该提案的目标是了解细胞环境在病毒感染中的作用。病毒生长所必需的细胞蛋白的鉴定将导致新的抗病毒治疗策略的开发。