Identifying Risk Factors for Leprosy Transmission Related to Co-infections, Unsafe WASH and Undernutrition Using Novel Serologic Multiplex and High Resolution Metabolomic Assays

项目摘要 在世界许多地区，麻风病作为一种高发病率的原因仍然资金不足，认识不足。 包括巴西在内的世界上发病率最高的国家之一， 每年有22，940例（2017年）。确定贫困相关因素对麻风病的影响的研究 被忽视的热带病（NTD），卫生条件差和营养不良等传播缺乏 全球麻风病研究竞技场，阻碍了消灭麻风病的进展。此外，更好地 为了取得进展，迫切需要监测战略和早期诊断工具。我们的集成 一系列的目标是通过使用最先进的血清学多重珠粒测定（MBA）来填补这些空白， 通过对麻风融合体的血清学反应性评估麻风分枝杆菌的社区负担 蛋白质，LID-1和高分辨率代谢组学（HRM），以确定早期感染的潜在标志物。到 为了实现这一目标，我们将对1,200名（年龄> 3岁）的人进行一次全社区的调查， 麻风病高发城市进行抗LID-1抗体检测， 地方性NTD，如血吸虫病、类圆线虫病和蛔虫病。合并本试验的结果 地理信息系统（GIS）将确定发病率和患病率的空间集群， 以及感染的环境风险因素。抗LID-1抗体阳性且匹配阴性者 对照组将参加一项为期3年的纵向研究（n=480），以确定麻风传播的危险因素， 包括合并感染、营养不良以及与水、环境卫生和个人卫生不良有关的因素 （WASH）。我们将进行为期六个月的随访，以确定新的麻风病例或麻风反应， 通过常规临床检查暴露于疾病，并将包括免疫测定（Th 1，Th 2， 和Th 17细胞因子），通过粪便虫卵和寄生虫检查进行蠕虫检测，以及微量营养素检测。最后，我们 第三个目标将使用高分辨率代谢组学（HRM）来识别内源性代谢物的代谢特征。 与M.麻风病可能导致 确定一种生物标志物，以在麻风病的早期阶段进行诊断。将进行HRM比较 在抗LID-1抗体阳性的没有活动性麻风病的个体中， 无症状抗LID-1阴性对照的小样本，目的是检测潜在的生物标志物 符合临床和亚临床麻风病HRM将在随访期间对任何 并在最后对剩余的无症状个体进行基线代谢组比较 那些患有活动性麻风病的人和那些没有的人。总之，这个真正的翻译项目将 直接影响巴西这些地区的麻风病控制，并将是第一个将不同的，但 互补、诊断和监测方法，以确定和量化相关的传播因素 这是实施有针对性的干预措施的关键一步。

Project Summary Leprosy remains underfunded and underrecognized as a cause of significant morbidity in many regions of the world including Brazil, which carries one of the highest incidence rates and the 2nd highest number of new cases annually (22,940 in 2017). Studies identifying the contribution of poverty-related factors to leprosy transmission such as neglected tropical diseases (NTDs), poor sanitation and undernutrition are lacking within the global leprosy research arena, stalling progress towards leprosy elimination. Furthermore, better surveillance strategies and tools for early diagnosis are critically needed to make progress. Our integrated series of aims seek to fill these gaps by using a state-of-the-art serological multiplex beaded assay (MBA) to assess the community burden of Mycobacterium leprae through serological reactivity to the leprosy fusion protein, LID-1 and high-resolution metabolomics (HRM) to identify potential markers for early infection. To accomplish this, we will implement a community-wide survey of 1,200 individuals (>age 3 years) from municipalities with high leprosy incidence to test for anti-LID-1 antibody as well as the presence of other endemic NTDs, such as schistosomiasis, strongyloidiasis, and ascariasis. Combining results from this assay with geographic information systems (GIS) will identify both spatial clusters of incidence and prevalence as well as environmental risk factors for infection. Those positive for anti-LID-1 antibody and matched negative controls will be enrolled in a 3-year longitudinal study (n=480) to identify risk factors for leprosy transmission, including co-infections, nutritional deficiencies and factors association with poor water, sanitation and hygiene (WASH). We will conduct six-month follow-ups to identify new leprosy cases or leprosy reactions in those exposed with disease through routine clinical examinations and will include immunologic assays (Th1, Th2, and Th17 cytokines), helminth testing via stool ova and parasite exams, and micronutrient testing. Lastly, our third aim will use high-resolution metabolomics (HRM) to identify metabolic signatures of endogenous metabolites related to macronutrient and energy metabolism associated with M. leprae that may lead to the identification of a biomarker to diagnose leprosy at its earliest stages. HRM will be performed to compare metabolic signatures in anti-LID-1 antibody positive individuals without active leprosy, this with leprosy and a small sample of asymptomatic anti-LID-1 negative controls with the goal of detecting potential biomarkers consistent with clinical and subclinical leprosy. HRM will be repeated during the follow-up period in any who develop leprosy and for remaining asymptomatic individuals at the end to compare the baseline metabolomes of those who developed active leprosy and those who did not. In conclusion, this truly translational project will directly impact leprosy control in these areas of Brazil and will be the first of its kind to integrate different, but complimentary, diagnostic and surveillance approaches to identify and quantify transmission factors associated with poverty, a critical step to implement targeted interventions.