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Roles of host RNA binding proteins in virus replication

宿主RNA结合蛋白在病毒复制中的作用

基本信息

批准号：
7340714
负责人：
PETER NAGY
金额：
$ 20.01万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7340714
关键词：
Affect Agriculture Animals Antiviral Agents Area Binding Biological Assay Biological Models Boxing Cataloging Catalogs Cells Complex Dengue Dengue Virus Development Disease Drug Delivery Systems EF-1alpha Elongation Factor Flavivirus Gene Delivery Genes Genetic Recombination Genome Genomics Glyceraldehyde-3-Phosphate Dehydrogenases Health Hepatitis A Virus Hepatitis C virus Homologous Gene Human In Vitro Integration Host Factors Knowledge Laboratories Lead Oxidoreductase Pestivirus Plants Play Positioning Attribute Proteins Proteomics RNA Binding RNA Helicase RNA Viruses RNA replication RNA-Binding Proteins RNA-Directed RNA Polymerase Replication-Associated Process Research Personnel Risk Role Site System Testing Tomatoes Tombusvirus Translations Viral Viral Pathogenesis Viral Physiology Viral Vaccines Virus Virus Diseases Virus Replication West Nile virus Work Yeast Model System Yeasts base design in vivo inorganic phosphate insight novel pathogen replicase research study size tomato bushy stunt virus vector viral RNA virus host interaction

项目摘要

DESCRIPTION: Plus-stranded RNA viruses, which pose significant risks to human health and cause major losses for agriculture, depend heavily on host factors to replicate in infected cells. The roles of the subverted host factors in virus replication are currently poorly understood due to the lack of tractable virus-host systems. To advance rapidly our understanding of virus-host interactions during viral replication, the investigator has developed the powerful Tomato bushy stunt virus (TBSV)-yeast model system that led to the identification of numerous host factors affecting viral replication. This application is aimed at dissecting the roles of three RNA-binding host proteins: glyceraldehyde-3-phosphate dehydrogenase (GAPDH), the p68 DEAD-box RNA helicase homolog Dpb2 and translation elongation factor EF-1alpha (Tef1/2p), all of which bind to TBSV RNA and also known to interact with Hepatitis C virus, West Nile virus, dengue 4 virus and hepatitis A virus RNAs, suggesting that host factors might play similar roles in replication of these viruses. The advantages of tombusviruses for replication studies are numerous, including (i) their simple genomes and robust replication; (ii) similarity of TBSV replicase proteins to proteins of important pathogens, such as HCV, West Nile virus and other flaviviruses and pestiviruses; (iii) availability of in vitro replication assays developed in the Investigator's laboratory; and (iv) the development by the investigator of an efficient yeast-based TBSV replication system. In addition, a recent genome-wide screen including 95% of all yeast genes identified host genes that affected TBSV accumulation. Based on these advances, TBSV is a premium model system to study the roles of host factors in virus replication in eukaryotic hosts. Due to the central role of virus replication in viral pathogenesis, the proposed studies on host RNA-binding proteins involved in virus replication promise to advance our understanding of the viral replication process and to lead to identification of new antiviral targets. These and similar studies are needed urgently, because our current knowledge on host factors involved in virus replication and in viral pathogenesis is incomplete. Knowledge of virus-host interactions and the roles of host RNA-binding proteins might reveal new drug targets and lead to development of novel antiviral strategies. The tractable in vitro and in vivo TBSV system developed by the investigator could prove beneficial to studies of other, less amenable RNA viruses.

描述：正链 RNA 病毒对人类健康构成重大风险，并给农业造成重大损失，在很大程度上依赖于宿主因子在受感染细胞中复制。由于缺乏易于处理的病毒宿主系统，目前对病毒复制中被破坏的宿主因子的作用知之甚少。为了快速推进我们对病毒复制过程中病毒与宿主相互作用的理解，研究人员开发了强大的番茄浓密矮化病毒（TBSV）-酵母模型系统，该系统识别了影响病毒复制的众多宿主因素。本应用旨在剖析三种 RNA 结合宿主蛋白的作用：3-磷酸甘油醛脱氢酶 (GAPDH)、p68 DEAD-box RNA 解旋酶同源物 Dpb2 和翻译延伸因子 EF-1α (Tef1/2p)，所有这些蛋白均与 TBSV RNA 结合，并且还与丙型肝炎病毒西尼罗河相互作用病毒、登革热 4 病毒和甲型肝炎病毒 RNA，表明宿主因素可能在这些病毒的复制中发挥相似的作用。烟草病毒在复制研究中的优势有很多，包括（i）其简单的基因组和强大的复制能力； (ii) TBSV复制酶蛋白与重要病原体蛋白的相似性，例如HCV、西尼罗河病毒和其他黄病毒和瘟病毒； (iii) 研究者实验室开发的体外复制测定的可用性； (iv) 研究人员开发了一种高效的基于酵母的 TBSV 复制系统。此外，最近的全基因组筛选（包括 95% 的酵母基因）确定了影响 TBSV 积累的宿主基因。基于这些进展，TBSV 是研究宿主因素在真核宿主病毒复制中的作用的优质模型系统。由于病毒复制在病毒发病机制中的核心作用，对参与病毒复制的宿主RNA结合蛋白的研究有望增进我们对病毒复制过程的理解，并导致新的抗病毒靶点的鉴定。迫切需要这些研究和类似的研究，因为我们目前对涉及病毒复制和病毒发病机制的宿主因素的了解还不完整。了解病毒与宿主的相互作用以及宿主 RNA 结合蛋白的作用可能会揭示新的药物靶点并导致新的抗病毒策略的开发。研究人员开发的易于处理的体外和体内 TBSV 系统可能有利于其他不太适合的 RNA 病毒的研究。