Innate immune factor in host susceptibility to rift valley fever virus

宿主对裂谷热病毒易感性的先天免疫因素

• 批准号: 8234941
• 负责人: James Walter Kazura
• 金额: $ 48.18万
• 依托单位: WASHINGTON 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/8234941
• 关键词: Accounting; Address; Affect; Africa; Africa South of the Sahara; Age; Animal Model; Antibodies; Antigens; Arboviruses; Area; Attenuated; Bioterrorism; Blood; Breathing; CD8B1 gene; Categories; Cellular Immunity; Chronic Disease; Clinical; Clinical Research; Communities; Culicidae; Demographic Factors; Dendritic Cells; Development; Disease; Disease Outcome; Encephalitis; Endothelium; Environmental Risk Factor; Epidemic; Epithelium; Epitopes; Event; Exposure to; Gene Frequency; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Heterogeneity; Human; Immune; Immune response; Immunity; Immunoglobulin G; In Vitro; Infection; Integration Host Factors; Interferon-alpha; Interferons; Investigation; Kenya; Knowledge; Laboratories; Ligands; Link; Livestock; Maintenance; Mediating; Middle East; Morbidity - disease rate; Mucous Membrane; Natural Immunity; Oral; Orthobunyavirus; Outcome; Participant; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Population; Positioning Attribute; Predisposition; Primates; Proteins; RNA; RNA Helicase; Recording of previous events; Recovery; Retinal; Retinal Diseases; Retinitis; Rift Valley fever virus; Risk; Risk Factors; Role; Route; Sampling; Serological; Severities; Site; Specific qualifier value; Structure of retinal pigment epithelium; Study Subject; System; T memory cell; T-Cell Activation; T-Lymphocyte; TLR3 gene; Testing; Translational Research; Up-Regulation; Venous; Viral; Viral Hemorrhagic Fevers; Viral Nonstructural Proteins; Viremia; Virus; Virus Diseases; adaptive immunity; aerosolized; animal tissue; base; biodefense; cellular targeting; clinical phenotype; conjunctiva; disease phenotype; epizootic; feeding; high risk; in vitro Model; lifetime risk; mortality; novel; pathogen; response; transmission process; tripolyphosphate; virus envelope

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.

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。该病毒具有很高的蓄意释放和传播潜力 生物恐怖主义，因为它可以通过吸入或与粘膜组织接触而雾化和传播 就像吸血的蚊子一样。由于缺乏忠实再现这一过程的小动物模型 人们对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知之甚少 关于先天免疫事件如何影响疾病发病机制和保护性适应性免疫 根据有限的观察，I 型干扰素反应延迟与严重疾病和死亡率相关。 这些知识差距将通过结合对肯尼亚裂谷热地区居民的研究来解决 流行病以大约 8 年的周期（最近的 2006-2007 年）发生，并具有体外感染和疾病模型 发病。我们观察到，裂谷热病毒在该地区向人类的传播远大于 此前怀疑，无论是在流行病期间还是流行病间歇期，终生患病风险高达 25% 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范围 （主要是视网膜炎）在早期、反复的裂谷热流行期间感染的人，并预先安排 必要的系统来测试患有和不患有裂谷热相关脑炎的患者组和/或 下次流行时出血热。在具体目标 2 中，我们将使用体外模型来定义先天性 免疫途径，例如受减毒 RVFV 影响的 TLR 和 RNA 解旋酶可识别关键细胞靶标 病毒接种、传播和发病的场所，例如口腔和结膜上皮，树突状 细胞、视网膜色素上皮和静脉内皮，并检查减弱的 RVFV 如何改变 树突状细胞向 T 细胞呈递抗原的能力。在具体目标 3 中，我们将检查这种关系 既往感染的血清学标志物与 RVFV 特异性 CD4+ 和 CD8+ T 细胞记忆之间，识别病毒 诱发 T 细胞记忆的表位，并将体外 PBMC 的先天性和适应性免疫反应与 RVFV 表位与视网膜炎的发展有关。在具体目标 4 中，我们将确定遗传因素如何 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。 总体而言，该项目将提供有关 RVFV 的先天性和适应性免疫如何的新信息 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。