Mechanism of Ebola Virus Pathogensis and Innate and Adpative Immunity

该项目的长期目标是了解宿主对埃博拉病毒感染的反应。要解决这个问题 问题，我们提出了一种系统生物学的方法，它将使用小鼠和猕猴感染模型，细胞 培养和生化分析，以及高通量基因组和蛋白质组分析，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。要确定其他 关键影响埃博拉病毒感染结局的宿主反应网络，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；后一项研究将 允许识别寄主易感等位基因。埃博拉病毒突变株将包括拥有 已知影响干扰素拮抗剂活性的VP24和VP35蛋白突变 蛋白质。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，丝状病毒感染研究的黄金标准。在目标3中，我们计划确定 埃博拉病毒疫苗诱导保护性免疫反应的机制。应聘者的出席率 保护小鼠和非人类灵长类免受致命剂量埃博拉病毒攻击的疫苗将允许 美国需要剖析保护的潜在机制。总的来说，拟议的研究将提供新的 对决定埃博拉病毒感染结果的宿主反应网络的洞察，并可能 这就提出了治疗埃博拉病毒感染的新方法。

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.