Pathogenesis of Uveitis in Ebola Virus Disease Survivors

埃博拉病毒病幸存者葡萄膜炎的发病机制

基本信息

批准号：
10490254
负责人：
Steven Yeh
金额：
$ 49.6万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10490254
关键词：
Activities of Daily Living Acute Address Africa African Anterior uveitis Antibodies Antibody Response Antigens Aqueous Humor B-Cell Activation B-Lymphocytes Blindness Blood Cells Cessation of life Clinical Clinical Research Complete Blindness Complication Country Decision Making Democratic Republic of the Congo Detection Development Diagnostic Disease Disease Outbreaks Ebola Ebola Hemorrhagic Fever Ebola virus Environment Epidemiology Evaluation Eye Eye diseases Future Haplotypes High Prevalence Homing Household Immune Immune response Immunity Immunoglobulin G Immunologic Markers Immunologics Immunology In Situ Hybridization Infection Inflammatory Investigation Laboratories Liquid substance Mediating Mental disorders Methodology Modeling Molecular Neuraxis Onset of illness Organ Panuveitis Pathogenesis Pathologic Patient Care Phenotype Plasma Population Control Prevalence Public Health Quality of life RNA Viruses Research Personnel Resolution Retinitis Reverse Transcriptase Polymerase Chain Reaction Risk Risk Factors Role Severity of illness Sierra Leone Specimen Suggestion Survivors T-Lymphocyte Techniques Testing Tissues United States Uveitis Viral Viral Antigens Viral Genome Viral Load result Virus Virus Diseases Vision Vitreous humor arthropathies clinical care diagnostic strategy disorder risk global health high risk human leukocyte antigen testing immune activation improved insight macrophage medical countermeasure molecular diagnostics molecular pathology nonhuman primate novel pandemic preparedness peripheral blood receptor reproductive organ response translational study

项目摘要

Project Summary/ Abstract Ebola virus disease (EVD) has been associated with a high prevalence of uveitis in EVD survivors in the wake of the unprecedented West African EVD outbreak from 2014-2016. The spectrum of disease ranges from anterior uveitis to sight-threatening panuveitis with complete blindness. The sheer number of EVD survivors impacted has given us the unique opportunity to characterize the clinical features, structural complications leading to vision loss, and pathogenesis of uveitis. Besides the significant impact of vision loss on quality-of- life and activities of daily living, uveitis associated with Ebola virus (EBOV) has scientific and public health implications because of our prior identification of EBOV in the aqueous humor. Beyond the recent outbreak in West Africa, two more recent outbreaks in Democratic Republic of Congo underscore the global health mandate to fully understand the clinical and scientific implications of EVD sequelae. Emerging clinical, basic, and translational investigation has provided insight regarding the potential mechanisms of uveitis associated with EVD. We recently described our novel methodology to safely interrogate aqueous humor specimens for EBOV in EVD survivors; while these ocular fluid specimens tested negative for EBOV by RT-PCR, recent molecular pathologic analysis of ocular tissue in a non-human primate EVD survivor model has demonstrated that EBOV persists within the vitreous humor in macrophages, and is associated with uveitis and retinitis. Additional compelling immunologic studies of an EVD survivor with uveitis showed Ebola-specific T-cell and B-cell activation with signs of ongoing Ebola antigen stimulation after plasma clearance of EBOV. These findings were suggestive of long-term EBOV persistence, which are detectable by systemic T- and B-cell responses. To further characterize the prevalence and clinical spectrum of uveitis, role of EBOV persistence and immunologic mechanisms of uveitis in EVD survivors, we propose three Aims: 1) In Aim 1, the prevalence of uveitis will be compared between EVD survivors and close contacts in Sierra Leone. Clinical factors and host risk factors including HLA-typing will be assessed to determine if there are clinical and host-related determinants of uveitis development. 2) In Aim 2, EBOV persistence will be assessed using reverse transcriptase polymerase chain reaction (RT- PCR testing) of vitreous fluid and in situ hybridization techniques to detect EBOV genome in the vitreous. 3) In Aim 3, Ebola-specific immune responses will be assessed in the blood and ocular fluid of EVD survivors with uveitis, specifically evaluating activation of Ebola-specific B and T-cells, IgG subclass composition. Insights from this study will define the spectrum of uveitis associated with EVD, assess whether EBOV is harbored in the vitreous, and advance our understanding of the interplay between infection and immunity in EVD. Ultimately, these findings will define diagnostic strategies and future medical countermeasures for EBOV, as well as other viruses that may establish persistence in the unique immune privileged ocular environment.

项目概要/摘要埃博拉病毒病 (EVD) 与埃博拉病毒病幸存者中葡萄膜炎的高患病率有关 2014 年至 2016 年西非史无前例的埃博拉病毒病爆发。疾病范围包括前葡萄膜炎至威胁视力的全葡萄膜炎并导致完全失明。埃博拉病毒病幸存者的绝对数量受影响给了我们独特的机会来描述临床特征、结构并发症导致视力丧失，并发病葡萄膜炎。除了视力丧失对生活质量的重大影响之外，埃博拉病毒（EBOV）相关葡萄膜炎具有科学性和公共卫生性由于我们之前在房水中鉴定出埃博拉病毒，因此产生了影响。除了最近爆发的疫情之外西非，刚果民主共和国最近爆发的两起疫情凸显了全球健康状况任务是充分了解埃博拉病毒病后遗症的临床和科学意义。新兴的临床、基础和转化研究提供了关于潜在潜力的见解与埃博拉病毒病相关的葡萄膜炎的机制。我们最近描述了我们的新颖方法来安全地检查埃博拉病毒病幸存者的房水样本中是否存在埃博拉病毒；当这些眼液样本被检测时最近对非人类灵长类动物眼组织进行分子病理分析，RT-PCR 检测结果为 EBOV 阴性 EVD 幸存者模型表明，埃博拉病毒持续存在于巨噬细胞的玻璃体液中，并且与葡萄膜炎和视网膜炎有关。针对患有葡萄膜炎的埃博拉病毒病幸存者的其他令人信服的免疫学研究显示埃博拉特异性 T 细胞和 B 细胞激活，并在血浆后出现持续埃博拉抗原刺激的迹象埃博拉病毒清除。这些发现表明埃博拉病毒长期存在，可通过以下方法检测到：全身 T 细胞和 B 细胞反应。为了进一步描述葡萄膜炎的患病率和临床谱，其作用为了研究埃博拉病毒的持久性和埃博拉病毒病幸存者葡萄膜炎的免疫机制，我们提出了三个目标： 1) 在目标 1 中，将比较塞拉利昂埃博拉病毒病幸存者和密切接触者之间葡萄膜炎的患病率莱昂内.将评估临床因素和宿主危险因素，包括 HLA 分型，以确定是否存在葡萄膜炎发展的临床和宿主相关决定因素。 2) 在目标 2 中，将使用逆转录酶聚合酶链式反应 (RT- 玻璃体液 PCR 检测和原位杂交技术检测玻璃体中的 EBOV 基因组。 3) 在目标 3 中，将评估埃博拉病毒病幸存者的血液和眼液中的埃博拉特异性免疫反应患有葡萄膜炎，专门评估埃博拉特异性 B 细胞和 T 细胞的激活、IgG 亚类组成。这项研究的见解将定义与埃博拉病毒病相关的葡萄膜炎的范围，评估埃博拉病毒是否是存在于玻璃体中，促进我们对玻璃体内感染和免疫之间相互作用的理解埃博拉病毒病。最终，这些发现将确定埃博拉病毒的诊断策略和未来的医疗对策，以及其他可能在独特的免疫特权眼部环境中建立持久性的病毒。