The Impact of Innate Neuronal Immunity on Neurotropic Arbovirus Pathogenesis

先天神经元免疫对嗜神经虫媒病毒发病机制的影响

• 批准号: 7497888
• 负责人: DAVID J MILLER
• 金额: $ 18.64万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-19 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7497888
• 关键词: Abbreviations; Alkaline Phosphatase; Alphavirus; Antiviral Agents; Antiviral Response; Apoptosis; Arbovirus Infections; Arboviruses; Bioinformatics; Bioterrorism; Categories; Cells; Central Nervous System Infections; Clinical; Complex; Culicidae; Data; Development; Encephalitis Viruses; Exhibits; Exposure to; Family; Genes; Genomics; Hour; Human; Immune; Immune response; Immune system; Immunity; In Vitro; Infection; Interferon Type I; Interferons; Knowledge; Luciferases; Mediating; Methods; Molecular; Morbidity - disease rate; Natural Immunity; Neuraxis; Neurons; Outcome; Pathogenesis; Pathway Analysis; Pathway interactions; Pattern recognition receptor; Personal Satisfaction; Pharmaceutical Preparations; Plasmids; Play; Poly I-C; Proteins; Public Health; RNA Viruses; RNA replication; Recovery; Response Elements; Role; Sindbis Virus; Small Interfering RNA; Structural Protein; System; Testing; Togaviridae; Toll-like receptors; Tretinoin; Validation; Venezuelan Equine Encephalitis Virus; Viral; Viral Pathogenesis; Virus; Virus Diseases; Western Equine Encephalitis Virus; Western Equine Encephalomyelitis; arbovirus disease; cell type; chemical genetics; design; high throughput screening; human TLR3 protein; melanoma; mortality; neurotropic; neurotropic virus; novel; pathogen; promoter; research study; response; small molecule; viral RNA

Description (provided by applicant): Innate cellular antiviral responses are essential first lines of defense against viral infections, and also play crucial roles in the initiation of adaptive immunity and hence eventual virus control or clearance. However, the inappropriate activation of innate immune responses can also contribute to viral pathogenesis. Intracellular pathways that suppress or potentiate steps in innate antiviral responses therefore represent crucial components of the host-pathogen interactions that ultimately determine the outcome of viral infections. Furthermore, a detailed understanding of the cellular and molecular mechanisms underlying these pathways is important for the rationale design of novel antiviral or immunomodulatory drugs. Although our knowledge regarding innate cellular antiviral responses has progressed tremendously over the past decade, significant gaps still exist. For example, innate antiviral immune responses consist of a complex network of interactions that exhibit both cell type- and pathogen-specific differences, but the functional significance and impact of these differences on viral pathogenesis, particularly within the central nervous system, have not been well studied. We hypothesize that intrinsic maturation-dependent innate antiviral responses are key determinants in the pathogenesis of neurotropic virus infections. We propose to explore these responses in human neuronal cells using western equine encephalitis virus (WEEV), a mosquito-borne positive-strand RNA virus belonging to the Togaviridae family (genus: Alphavirus). WEEV and the closely related eastern and Venezuelan equine encephalitis viruses are category B bioterrorism agents, and cause central nervous system infections that are associated with high clinical morbidity and mortality for which there are no effective therapies. Arboviral diseases, such as those caused by neurotropic alphaviruses, have also seen both an emergence and resurgence as significant public health threats over the past several decades. The long-term objectives of this project are to elucidate the molecular mechanisms underlying the cell- autonomous recognition, activation, and effector pathways involved in the innate antiviral responses of human central nervous system neurons to arbovirus infections. The focus of this proposal is to employ targeted and global genetic and chemical genomic approaches with cultured human neuronal cells to examine the activation pathways responsible for WEEV recognition and initiation of innate antiviral responses in mature neurons.

描述（由申请方提供）：先天性细胞抗病毒应答是抵抗病毒感染的基本第一道防线，并且在启动适应性免疫以及最终控制或清除病毒方面也起着关键作用。然而，先天性免疫应答的不适当激活也可促成病毒发病机制。因此，抑制或加强先天性抗病毒反应步骤的细胞内途径代表了最终决定病毒感染结果的宿主-病原体相互作用的关键组成部分。此外，详细了解这些途径的细胞和分子机制对于设计新型抗病毒或免疫调节药物的理论基础非常重要。虽然我们对先天性细胞抗病毒反应的认识在过去十年中取得了巨大进展，但仍然存在重大差距。例如，先天性抗病毒免疫反应由一个复杂的相互作用网络组成，这些网络表现出细胞类型和病原体特异性差异，但这些差异对病毒发病机制的功能意义和影响，特别是在中枢神经系统内，尚未得到很好的研究。我们推测，内在的成熟依赖性先天抗病毒反应是嗜神经病毒感染的发病机制的关键决定因素。我们建议使用西方马脑炎病毒（WEEV），蚊子传播的正链RNA病毒属于披膜病毒科（属：甲病毒）的人类神经元细胞中探索这些反应。WEEV和密切相关的东部和委内瑞拉马脑炎病毒是B类生物恐怖剂，并引起中枢神经系统感染，其与高临床发病率和死亡率相关，对此没有有效的治疗方法。虫媒病毒疾病，如嗜神经性甲病毒引起的疾病，在过去几十年中也作为重大的公共卫生威胁出现和死灰复燃。本项目的长期目标是阐明人类中枢神经系统神经元对虫媒病毒感染的先天性抗病毒反应中涉及的细胞自主识别、激活和效应途径的分子机制。该提案的重点是采用培养的人类神经元细胞的靶向和全局遗传和化学基因组方法，以检查负责WEEV识别和启动成熟神经元中先天性抗病毒反应的激活途径。