Innate immune factor in host susceptibility to rift valley fever virus

裂谷热病毒是一种A类虫媒病毒病原体，可引起出血热、视网膜炎和 非洲和中东的脑炎。这种病毒极有可能被故意释放， 生物恐怖主义，因为它也可以通过吸入或与粘膜组织接触而雾化和传播 就像吸血蚊子一样由于缺乏一个小动物模型，忠实地概括了 由于人类感染的结果多种多样，而且裂谷热流行病发生在偏远地区， 关于先天免疫事件如何有助于疾病的发病机制和保护性适应性免疫 从有限的观察，延迟I型IFN反应与严重疾病和死亡率有关。 将通过对肯尼亚一个地区的居民进行研究来弥补这些知识上的差距，该地区存在裂谷热， 流行病以约8年为一个周期（最近的一次是2006-2007年）发生，采用体外感染和疾病模型 发病机制我们观察到RVFV在该地区传播给人类的比例远远高于 以前怀疑，无论是在流行和流行之间的时期，高达25%的终身风险， 感染在具体目标1中，我们将定义慢性病表型的风险因素和谱 （主要是视网膜炎），并预先定位 测试患有和不患有RVF相关脑炎的患者组的必要系统和/或 在下一次流行病期间出现出血热。在具体目标2中，我们将使用体外模型来定义先天性 受减毒RVFV影响的免疫途径，例如TLR和RNA解旋酶，可以识别关键的细胞靶点 病毒接种、传播和发病部位，例如口腔和结膜上皮，树突状细胞 细胞，视网膜色素上皮和静脉内皮细胞，并检查如何衰减RVFV改变 树突状细胞向T细胞呈递抗原的能力。在具体目标3中，我们将研究 在先前感染的血清学标志物与RVFV特异性CD 4+和CD 8 + T细胞记忆之间， 表位，引发T细胞记忆，并在体外PBMC先天性和适应性免疫反应， RVFV表位与视网膜炎的发展。在具体目标4中，我们将确定遗传 先天免疫的多态性解释了视网膜炎结果和适应性免疫的异质性。 总的来说，这个项目将提供新的信息，关于先天性和适应性免疫RVFV 确定暴露于这种A类病原体的高风险人群的感染和疾病结果。

Rift Valley fever virus is a Category A arbovirus pathogen that causes hemorrhagic fever, retinitis and encephalitis in Africa and the Middle East. The virus has high potential for deliberate release and bioterrorism since it may be aerosolized and transmitted by inhalation or contact with mucosal tissue as well as by blood-feeding mosquitoes. Given the lack of a small animal model that faithfully recapitulates the diverse outcomes of human infection and the fact that RVF epidemics occur in remote areas, little is known about how innate immune events contribute to disease pathogenesis and protective adaptive immunity aside from limited observations that delayed type I IFN responses are associated with severe illness and mortality. These gaps in knowledge will be addressed by combining study of residents of an area of Kenya where RVF epidemics occur in ~8-year cycles (most recently 2006-2007) with in vitro models of infection and disease pathogenesis. We have observed that RVFV transmission to humans in this area is much greater than previously suspected, both during epidemic and inter-epidemic periods, with up to 25% lifetime risk of infection. In Specific Aim 1 we will define the risk factors for and spectrum of chronic disease phenotypes (primarily retinitis) in persons infected during earlier, repeated RVF epidemics and pre-position the necessary systems to test panels of patients with and without RVF-associated encephalitis and/or hemorrhagic fever during the next epidemic. In Specific Aim 2 we will use in vitro models to define the innate immune pathways, e.g. TLR and RNA helicases, affected by attenuated RVFV, identify key cellular targets at sites of viral inoculation, dissemination and pathogenesis, e.g. oral and conjunctiva epithelium, dendritic cells, retinal pigmented epithelium and venous endothelium, and examine how attenuated RVFV alters the ability of dendritic cells to present antigen to T cells. In Specific Aim 3 we will examine the relationship between serologic markers of prior infection and RVFV-specific CD4+ and CD8+ T cell memory, identify viral epitopes that elicit T cell memory, and correlate in vitro PBMC innate and adaptive immune responses to RVFV epitopes with the development of retinitis. In Specific Aim 4 we will determine how genetic polymorphism of innate immunity accounts for heterogeneity in retinitis outcomes and adaptive immunity. Overall this project will provide novel information regarding how innate and adaptive immunity to RVFV determines infection and disease outcomes in humans at high-risk for exposure to this Category A pathogen.