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

• 批准号: 10224207
• 负责人: Steven Yeh
• 金额: $ 60.43万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 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/10224207
• 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; Structure; 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; 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

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.

项目总结/摘要 埃博拉病毒病（EVD）与EVD幸存者中葡萄膜炎的高患病率相关， 2014-2016年西非前所未有的埃博拉病毒病爆发。疾病的范围从 从前葡萄膜炎到威胁视力的全葡萄膜炎，导致完全失明。EVD幸存者的绝对数量 撞击给了我们独特的机会来描述临床特征，结构性并发症 导致视力丧失和葡萄膜炎的发病机制。除了视力丧失对视力质量的显著影响外， 生活和日常生活活动，葡萄膜炎与埃博拉病毒（EBOV）有科学和公共卫生 这是因为我们先前在眼房水中鉴定出EBOV。除了最近爆发的 西非、刚果民主共和国最近爆发的两起疫情凸显了全球卫生 任务是充分了解EVD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的 与EVD相关的葡萄膜炎的机制。我们最近描述了我们的新方法， 询问EVD幸存者中的EBOV的房水样本;而这些眼液样本测试 通过RT-PCR对EBOV呈阴性，最近对非人灵长类动物眼组织的分子病理学分析 EVD存活者模型已经证明，EBOV在巨噬细胞中的玻璃体液内持续存在，并且在巨噬细胞中存在。 与葡萄膜炎和视网膜炎有关。EVD幸存者葡萄膜炎的其他引人注目的免疫学研究 显示埃博拉特异性T细胞和B细胞活化，血浆后有持续埃博拉抗原刺激的迹象。 清除EBOV。这些发现提示了EBOV的长期持续性，其可通过免疫组织化学检测。 全身性T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，作用 EBOV的持久性和EVD幸存者葡萄膜炎的免疫机制，我们提出了三个目的： 1)在目标1中，将比较塞拉利昂EVD幸存者和密切接触者之间的葡萄膜炎患病率 里昂将评估临床因素和宿主风险因素（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反应（RT-PCR）评估EBOV持久性。 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，将在EVD幸存者的血液和眼液中评估埃博拉特异性免疫应答 与葡萄膜炎，特别是评价埃博拉病毒特异性B和T细胞的激活，IgG亚类组成。 这项研究的见解将定义与EVD相关的葡萄膜炎的光谱，评估EBOV是否是 隐藏在玻璃体中，并推进我们对感染和免疫之间相互作用的理解， EVD。最终，这些发现将确定EBOV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环境中建立持久性的病毒。