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（由申请人提供）：先天的细胞抗病毒反应是针对病毒感染的必要第一线，并且在自适应免疫的启动中起着至关重要的作用，因此最终的病毒控制或清除率。但是，先天免疫反应的不当激活也会导致病毒发病机理。因此，抑制或增强先天抗病毒反应中抑制或增强步骤的细胞内途径代表了宿主 - 病原体相互作用的关键成分，这些组成最终决定了病毒感染的结果。此外，对这些途径的细胞和分子机制的详细理解对于新型抗病毒或免疫调节药物的基本原理设计很重要。尽管在过去的十年中，我们对先天细胞抗病毒反应的知识却取得了巨大发展，但仍然存在很大的差距。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，这些相互作用既表现出细胞类型和病原体特异性差异，但是这些差异对病毒发病机理的功能意义和影响，尤其是在中枢神经系统中，尚未得到很好的研究。我们假设内在的成熟依赖性先天抗病毒反应是神经性病毒感染发病机理中的关键决定因素。我们建议使用西马脑炎病毒（WEEV）探索人类神经元细胞中的这些反应，这是一种蚊子 - 传播的阳性链链RNA病毒，属于Togaviridae家族（属：α）。 WEEV以及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，并且引起中枢神经系统感染，与没有有效疗法的临床发病率和死亡率高有关。在过去的几十年中，弧菌疾病，例如由神经型α病毒引起的疾病，也将出现和复兴视为重要的公共卫生威胁。该项目的长期目标是阐明人类中枢神经系统神经元对arbovirus感染的先天抗病毒反应所涉及的细胞自主识别，激活和效应途径的分子机制。该提案的重点是使用培养的人神经元细胞采用靶向和全球遗传和化学基因组方法来检查导致成熟神经元中先天性抗病毒反应的导致WEEV识别和启动的激活途径。