Mechanism of Ebola Virus Pathogensis and Innate and Adpative Immunity

埃博拉病毒致病机制及先天性和适应性免疫

• 批准号: 7676430
• 负责人: YOSHIHIRO KAWAOKA
• 金额: $ 53.85万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-20 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7676430
• 关键词: Adaptor Signaling Protein; Address; Affect; Alleles; Animals; Antiviral Agents; Antiviral Response; Biochemical; Biological Assay; Canada; Cell Culture Techniques; Clinical Pathology; Collaborations; Data; Development; Dose; Ebola Vaccines; Ebola virus; Ensure; Family; Filovirus; Gene Expression; Gene Proteins; Genes; Genomics; Glycoproteins; Goals; Gold; Health; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunologics; Infection; Inflammatory; Influenza A Virus, H5N1 Subtype; Interferon Activation; Interferons; Kinetics; Knock-out; Knockout Mice; Licensing; Macaca; Modeling; Morbidity - disease rate; Mus; Mutation; NF-kappa B; Natural Immunity; Outcome; Pacific Northwest; Pathway interactions; Pattern recognition receptor; Phosphorylation; Play; Predisposition; Process; Proteins; Proteomics; RNA Virus Infections; Role; SARS coronavirus; Science; Signal Pathway; Signal Transduction; Sterility; System; TLR7 gene; Testing; Therapeutic Intervention; Toll-like receptors; Universities; Vaccination; Vaccines; Variant; Vesicular stomatitis Indiana virus; Virion; Virus Diseases; Virus-like particle; Washington; Wild Type Mouse; Work; base; cytokine; high throughput screening; influenzavirus; insight; metabolomics; mortality; mutant; nonhuman primate; novel; novel strategies; pathogen; prevent; response; transcription factor; vaccine candidate; virology

The long-term goal of this project is to understand host responses to Ebolavirus infections. To address this question, we propose a 'Systems Biology1 approach that will use mouse and macaque infection models, cell culture and biochemical assays, and high-throughput genomic and proteomic analyses to identify cellular response networks to Ebolavirus infection, and the underlying features of protective immunity afforded by successful vaccination. In Aim 1, we will assess the contribution of RIG-I and TLR3/7-signaling to innate immune responses to Ebolavirus infection. RIG-I and TLR3/7 signaling pathways are now recognized as major players in innate immune responses; their significance for innate immune responses to Ebolavirus infections, however, is currently unknown and will therefore be addressed in this aim. To identify additional host response networks that critically affect the outcome of Ebolavirus infections, we will test wild-type and mutant Ebolaviruses in wild-type, knock-out, and genetically diverse mice in Aim 2; the latter studies will allow the identification of host susceptibility alleles. Ebolavirus mutants will include variants possessing mutations in the VP24 and VP35 proteins which are known to affect the interferon antagonist activity of these proteins. Moreover, we will carry out infection, genomics, proteomics, and metabolomics studies in nonhuman primates, the gold standard for filovirus infection studies. In Aim 3, we plan to determine the mechanisms of protective immune responses induced by Ebolavirus vaccines. The availability of a candidate vaccine that protects mice and nonhuman primates from challenge with lethal doses of Ebolavirus will allow us to dissect the underlying mechanisms for protection. Collectively, the proposed studies will provide novel insights into the network of host responses that determine the outcome of Ebolavirus infections, and may thus suggest novel approaches to the treatment of Ebolavirus infections.

该项目的长期目标是了解宿主对埃博拉病毒感染的反应。解决这个问题 问题，我们提出了一种'系统生物学1方法，该方法将使用鼠标和猕猴感染模型，细胞 培养和生化测定，以及高通量基因组和蛋白质组学分析以鉴定细胞 对埃博拉病毒感染的反应网络以及保护性免疫的基本特征 成功的疫苗接种。在AIM 1中，我们将评估RIG-I和TLR3/7信号对先天的贡献 对埃博拉病毒感染的免疫反应。 RIG-I和TLR3/7信号通路现在被认为是 先天免疫反应的主要参与者；它们对先天免疫反应的意义 但是，目前未知感染，因此将在此目标中解决。确定其他 严重影响埃博拉病毒感染结果的宿主反应网络，我们将测试野生型和 AIM 2中的野生型，敲除和遗传多样的小鼠中的突变埃博氏病；后一个研究将 允许识别宿主易感性等位基因。埃博拉病毒突变体将包括具有的变体 VP24和VP35蛋白的突变，已知会影响这些干扰素拮抗剂的活性 蛋白质。此外，我们将进行感染，基因组学，蛋白质组学和代谢组学研究 非人类灵长类动物，是丝状病毒感染研究的黄金标准。在AIM 3中，我们计划确定 由埃博拉病毒疫苗诱导的保护性免疫反应的机制。候选人的可用性 保护小鼠和非人类灵长类动物免受挑战的疫苗，埃博氏病毒将允许 我们剖析了保护的基本机制。拟议的研究集体将提供新颖 对确定埃博拉病毒感染结果的宿主反应网络的见解，可能 因此，提出了治疗埃博拉病毒感染的新方法。