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.

裂谷发烧病毒是一种导致出血热，视网膜炎和 非洲和中东的脑炎。该病毒具有很高的故意释放潜力和 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被雾化和传播 就像喂蚊子一样。鉴于缺乏小型动物模型，该模型忠实地概括了 人类感染的各种结果以及RVF流行病发生在偏远地区，鲜为人知的事实 关于先天免疫事件如何有助于疾病发病机理和保护性适应性免疫 从有限的观察结果表明，延迟I型IFN反应与严重疾病和死亡率有关。 这些知识的差距将通过结合肯尼亚地区居民的研究来解决RVF的居民 流行病发生在〜8年的周期（最近2006- 2007年）中，并具有体外感染和疾病模型 发病。我们已经观察到，RVFV向该地区的人类传播远大于 以前怀疑在流行病和流行期间，终身风险高达25％ 感染。在特定目标1中，我们将定义慢性疾病表型的危险因素和频谱 （主要是视网膜炎）在早期感染的人中，重复的RVF流行病和预位 测试患有和没有RVF相关脑炎和/或患有和/或没有RVF相关脑炎的患者面板的必要系统 下一个流行病期间出血热。在特定目标2中，我们将使用体外模型来定义先天 免疫途径，例如受衰减RVFV影响的TLR和RNA解旋酶确定关键的细胞靶标 病毒接种，传播和发病机理的部位，例如口服和结膜上皮，树突状 细胞，视网膜色素上皮和静脉内皮，检查RVFV如何改变RVFV 树突状细胞对T细胞呈抗原的能力。在特定目标3中，我们将检查关系 在先前感染的血清学标记和RVFV特异性CD4+和CD8+ T细胞存储器之间，识别病毒 引起T细胞记忆并在体外PBMC先天和适应性免疫反应的表位与 RVFV表位随视网膜炎的发展。在特定目标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局和适应性免疫的异质性。 总体而言，该项目将提供有关先天性和适应性免疫力RVFV的新颖信息 确定在高风险中人类的感染和疾病结局，以暴露于该类别的病原体。