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: 8234064
• 负责人: YOSHIHIRO KAWAOKA
• 金额: $ 62.41万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8234064
• 关键词: Adaptor Signaling Protein; Address; Affect; Alleles; Antiviral Agents; Antiviral Response; Biochemical; Cell Culture Techniques; Collaborations; Data; Development; Dose; Ebola Vaccines; Ebola virus; Family; Filovirus; Gene Proteins; Genes; Genomics; Glycoproteins; Goals; Gold; Immune; Immune response; Immunity; Immunologics; Infection; Inflammatory; Influenza A Virus, H5N1 Subtype; Interferon Activation; Interferons; Kinetics; Knock-out; Knockout Mice; Licensing; Macaca; Modeling; 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; Signal Pathway; Signal Transduction; System; TLR3 gene; 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; induced pluripotent stem cell; influenzavirus; insight; metabolomics; mutant; nonhuman primate; novel; novel strategies; pathogen; prevent; response; transcription factor; vaccine candidate

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。为了解决这个 问题，我们提出了一个“系统生物学1方法，将使用小鼠和猕猴感染模型，细胞 培养和生物化学测定，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 成功接种疫苗在目标1中，我们将评估RIG-I和TLR 3/7信号转导对先天性免疫缺陷的贡献。 埃博拉病毒感染的免疫反应。RIG-I和TLR 3/7信号通路现在被认为是 先天免疫反应的主要参与者;它们对埃博拉病毒先天免疫反应的意义 然而，感染目前尚不清楚，因此将在这一目标中加以解决。努力查明还 宿主反应网络，严重影响埃博拉病毒感染的结果，我们将测试野生型和 Aim 2中野生型、基因敲除和遗传多样性小鼠中的突变埃博拉病毒;后面的研究将 允许鉴定宿主易感性等位基因。埃博拉病毒突变体将包括具有以下特征的变体： VP 24和VP 35蛋白中的突变，这些突变已知影响这些蛋白的干扰素拮抗剂活性， proteins.此外，我们还将开展感染、基因组学、蛋白质组学和代谢组学研究， 非人灵长类动物，丝状病毒感染研究的金标准。在目标3中，我们计划确定 埃博拉病毒疫苗诱导的保护性免疫应答的机制。候选人的可用性 保护小鼠和非人灵长类动物免受致命剂量埃博拉病毒攻击的疫苗将允许 剖析保护的潜在机制。总的来说，拟议的研究将提供新的 深入了解决定埃博拉病毒感染结果的宿主反应网络， 因此提出了治疗埃博拉病毒感染的新方法。