Impact of ocular microbiome, immune response and Chlamydiae on trachoma following MDA

项目摘要 沙眼衣原体（Ct）是当今世界上感染性失明的主要原因。世界卫生 世界卫生组织（WHO）估计，全球有超过1.42亿人面临不可逆转的视力丧失风险。这 这一数字可能低估了真实数字，因为很难说明所有受影响的社区 在全球由沙眼衣原体引起的眼部疾病称为沙眼，每年的价格约为 80亿美元的损失。这一被忽视的疾病最集中的国家包括37个国家， 非洲、中东、亚洲、中南美沿着还有澳大利亚。非洲拥有超过89%的 世界上已知的沙眼病例中，反映了健康差距的主要地区。世卫组织开发了SAFE 到2020年消除沙眼这一公共卫生问题的战略。您申请的职位： 内翻睫毛（称为沙眼倒睫或TT）;治疗Ct的抗生素;面部清洁， 改善卫生和环境以减少传播。SAFE的A部分包括质量 阿奇霉素与美国国家药品监督管理局（MDA）联合使用，已在许多国家使用。10种地方病或 世卫组织已确认低流行国家无沙眼。然而，6个地方病和38个 高流行国家没有，尽管它们接受了5至10多轮MDA。负担最重 在埃塞俄比亚和南苏丹，约30-50%的10岁以下儿童患有活跃的 沙眼，其原因尚不清楚。沙眼作为一个公共卫生问题不会被消除 直到我们理解为什么在高流行性的人群中，在多轮MDA治疗后， 国家因此，我们的统一假设是，沙眼的自然史是由 受影响的眼部微生物组、免疫反应和病原体群体（Ct和非Ct） MDA的。虽然对眼部微生物组的研究越来越多，但很少有研究评估 健康和沙眼眼睛之间的微生物群组成的差异， CT感染的影响。我们将采用宏基因组鸟枪测序（MSS）来了解健康， 除了免疫反应和病原体基因组外， 图1是居住在埃塞俄比亚的沙眼高流行性阿姆哈拉地区的队列的特征。我们的目标是：1） 基于全基因组测序检查Ct感染; 2）鉴定Ct感染的分类多样性和丰度。 有和没有衣原体的受试者的眼部微生物群及其与沙眼疾病的关系; 和3）确定与衣原体相关和不与衣原体相关的宿主微生物群/免疫应答谱，和 开发模型来预测MDA后的沙眼。这项工作将自然过渡到改善衣原体 使用MSS方法的诊断，并制定干预措施， 可能包括新的治疗策略和/或修订的治疗持续时间，以减少和消除 非洲高危人群中的高流行性沙眼最需要干预。

PROJECT SUMMARY Chlamydia trachomatis (Ct) is the leading cause of infectious blindness in the world today. The World Health Organization (WHO) estimates that there are over 142 million people at risk of irreversible loss of sight. This figure likely underestimates the true numbers as it is difficult to account for all communities that are affected globally. The ocular disease caused by Ct is called trachoma and carries an annual price tag of approximately $8 billion from lost productivity. The highest concentrations of this neglected disease include 37 countries in Africa, the Middle East, Asia, and Central and South America along with Australia. Africa has over 89% of the world’s known trachoma cases, reflecting a major region of health disparity. The WHO developed the SAFE strategy to eliminate trachoma as a public health problem by the year 2020. SAFE stands for: Surgery to correct in-turned eyelashes (known as Trachomatous Trichiasis or TT); Antibiotics to treat Ct; Facial cleanliness to improve hygiene, and Environmental improvements to reduce transmission. The A part of SAFE includes Mass Drug Administration (MDA) with azithromycin and has been used in many countries. Ten endemic or hypoendemic countries have been validated by WHO as being trachoma free. However, 6 endemic and 38 hyperendemic countries have not, although they have received 5 to over 10 rounds of MDA. The highest burden of disease is in Ethiopia and South Sudan where ~30-50% of children under 10 years of age have active trachoma, and the reasons for this remain unclear. Trachoma as a public health concern will not be eliminated until we understand why there is ongoing active trachoma following multiple rounds of MDA in hyperendemic countries. Our unifying hypothesis, therefore, is that the natural history of trachoma is defined by the interaction of the ocular microbiome, immune responses and pathogen populations (both Ct and non-Ct) that are influenced by MDA. While there is a growing body of research on the ocular microbiome, few studies have evaluated differences in microbiota composition between healthy and trachomatous eyes and none have looked at the influence of Ct infection. We will employ metagenome shotgun sequencing (MSS) to understand healthy, dysbiotic and chlamydial-associated microbiota in addition to immune responses and pathogen genomic characteristics for a cohort residing in the trachoma hyperendemic Amhara Region of Ethiopia. We aim to: 1) Examine Ct infections based on whole genome sequencing; 2) Identify taxonomic diversity and abundance of ocular microbiota among subjects with and without Chlamydia and their association with trachomatous disease; and 3) Determine host microbiota/immune response profiles associated with and without Chlamydia, and develop models to predict trachoma post MDA. This work will naturally transition to improving chlamydial diagnostics that utilize MSS methods, and developing interventions that, given the ineffective antibiotic regimens to date, may include novel therapeutic strategies and/or revised treatment duration to decrease and eliminate hyperendemic trachoma among at risk populations in Africa that have the greatest need for intervention.