Systems Biology Identifies Restriction Factors for West Nile Virus

系统生物学确定西尼罗河病毒的限制因素

• 批准号: 8579950
• 负责人: Michael S Diamond
• 金额: $ 45.1万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8579950
• 关键词: Accounting; Affect; Animals; Arboviruses; Area; Attenuated; Biological; Categories; Cell physiology; Cells; Collaborations; Complement; Complex; Computer Simulation; Cultured Cells; Dengue Virus; Development; Disease; Disease Outbreaks; Disease Outcome; Ebola virus; Ectopic Expression; Evaluation; Flavivirus; Flavivirus Infections; Gene Deletion; Gene Silencing; Gene Targeting; Generations; Genes; Genetic Variation; Growth; Human; Human Virus; Immune; Immune response; Immunity; In Vitro; Individual; Infection; Infection Control; Influenza; Instruction; Integration Host Factors; Japanese encephalitis virus; Kinetics; Life Cycle Stages; Messenger RNA; MicroRNAs; Modeling; Mus; Organism; Pathogenesis; Pathway Analysis; Pathway interactions; Pattern; Phenotype; Predisposition; Process; Proteome; Proteomics; RNA Virus Infections; RNA Viruses; Research Project Grants; Resources; Risk; Staging; Survival Analysis; System; Systems Biology; Testing; Therapeutic Agents; Tissues; United States National Institutes of Health; Variant; Viral; Viral Load result; Virulence; Virulent; Virus; Virus Diseases; West Nile virus; Work; base; cell type; data management; gain of function; in vivo; insight; loss of function; member; metabolomics; network models; novel; novel strategies; pathogen; programs; research study; validation studies; virus pathogenesis

PROJECT SUMMARY (See instructions): Members of the Flavivirus genus are the most important arthropod-borne viruses causing disease in humans, many of which are characterized as NIH Category A, B, and C organisms. This genus includes viruses [West Nile virus (WNV), Japanese encephalitis virus (JEV) and Dengue virus (DENV)] that are endemic and continue to spread in many areas of the world. Flaviviruses account for -100 millions infections per year, with billions at risk and no specific therapy available. Although much work has focused on understanding the mechanisms of flavivirus replication in cultured cells, and on defining virulence in vivo, less remains known about host responses to strains of different virulence, and the genes and cell types that modulate infection in vivo. Here, we propose to identify and define the mechanism of action of novel host genes that modulate WNV infection. A systems biology approach to studying complex host-pathogen interactions associated with infection by virulent and attenuated WNV strains will provide new insight into host response mechanisms. With the support of several Cores (computational; proteomics, metabolomics, and lipidomics; data management and resources dissemination), we will acquire a global picture of the host response to infection by WNV strains of distinct pathogenic potential. Such an analysis has never been performed for any flavivirus. This approach to studying WNV pathogenesis will interact directly with work in Project 1 on influenza A and Ebola viruses to identify novel common genes, networks, and pathways that restrict infection with the viruses studied here. Target genes identified by systems biology will be validated in cells using ectopic expression and gene silencing, and these phenotypes will help prioritizing the generation of new KO mice for evaluation of the function of target genes in vivo in the context of WNV infection. Overall, our studies will provide new insight into the cellular processes that restrict infection by WNV and likely other viruses, and thus may promote novel strategies for development of therapeutic agents that contain virus spread and disease. Moreover, it may have implications for understanding the genetic variation in humans, which could explain susceptibility to particular viral infections.

项目摘要(见说明)：黄病毒属成员是导致人类疾病的最重要的节肢动物传播病毒，其中许多被描述为NIH A、B和C类生物。该属包括地方性病毒[西尼罗河病毒(WNV)、日本脑炎病毒(JEV)和登革病毒(DENV)]，并继续在世界许多地区传播。黄病毒每年造成1亿人感染，数十亿人面临风险，而且没有专门的治疗方法。虽然许多工作都集中在了解黄病毒在培养细胞中的复制机制，以及在体内定义毒力，但对宿主对不同毒力菌株的反应以及体内调节感染的基因和细胞类型仍知之甚少。在这里，我们建议识别和定义调节西尼罗河病毒感染的新宿主基因的作用机制。用系统生物学的方法研究与西尼罗河病毒强毒株和弱毒株感染相关的复杂宿主-病原体相互作用将为宿主反应机制提供新的见解。在几个核心(计算；蛋白质组学、代谢组学和脂质组学；数据管理和资源传播)的支持下，我们将获得宿主对具有不同致病潜力的WNV毒株感染的全球反应图景。从未对任何黄病毒进行过这样的分析。这种研究西尼罗河病毒致病机理的方法将直接与项目1中关于甲型流感和埃博拉病毒的工作相互作用，以确定限制感染这里研究的病毒的新的共同基因、网络和途径。系统生物学确定的目标基因将通过异位表达和基因沉默在细胞中得到验证，这些表型将有助于优先生成新的KO小鼠，以便在西尼罗河病毒感染的背景下评估目标基因在体内的功能。总体而言，我们的研究将为限制西尼罗河病毒和可能的其他病毒感染的细胞过程提供新的见解，从而可能促进开发包含病毒传播和疾病的治疗剂的新策略。此外，它可能对理解人类的遗传变异有影响，这可能解释对特定病毒感染的易感性。