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。该病毒很有可能被故意释放，并 生物恐怖主义，因为它可能被雾化并通过吸入或接触粘膜组织传播 就像吃血的蚊子一样。鉴于缺乏一种小动物模型来忠实地概括 人类感染的不同结果以及裂谷热流行发生在偏远地区的事实，人们知之甚少 关于先天免疫事件如何在疾病发病机制和保护性适应性免疫中起作用 根据有限的观察，延迟的I型干扰素反应与严重疾病和死亡率有关。 这些知识上的差距将通过结合对肯尼亚RVF地区居民的研究来解决 流行病以大约8年的周期(最近一次是2006-2007年)通过体外感染和疾病模型发生 发病机制。我们观察到，RVFV在这一地区对人类的传播远远大于 以前怀疑，在流行期间和流行间歇期，有高达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危险因素和谱系 (主要是视网膜炎)在早期反复的裂谷热流行期间感染的人，并预先放置 测试患有和不患有裂谷热相关性脑炎和/或脑炎的患者的必要系统 下一次流行期间的出血热。在特定目标2中，我们将使用体外模型来定义先天的 受减毒活病毒影响的免疫途径，如TLR和RNA解旋酶，识别关键的细胞靶点 病毒接种、传播和致病部位，如口腔和结膜上皮、树突 细胞，视网膜色素上皮和静脉内皮细胞，并检查减毒活病毒如何改变 树突状细胞向T细胞递呈抗原的能力。在具体目标3中，我们将考察两者之间的关系 在既往感染的血清学标志物和RVFV特异性的CD4+和CD8+T细胞记忆之间，识别病毒 激发T细胞记忆的表位，并在体外将PBMC天然和获得性免疫反应关联到 RVFV表位随着视网膜炎的发生而发展。在具体目标4中，我们将确定基因如何 天然免疫的多态解释了视网膜病变结果和获得性免疫的异质性。 总体而言，该项目将提供有关RVFV的先天免疫和获得性免疫的新信息 确定接触这种A类病原体的高危人群的感染和疾病结局。

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.