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 麻风病仍然资金不足，而且没有被认为是导致麻风病严重发病率的一个原因。 包括巴西在内的世界上，巴西是发病率最高的国家之一，也是新发病例数量第二多的国家 每年的案件(2017年为22,940起)。确定与贫困有关的因素对麻风的贡献的研究 国内缺乏被忽视的热带病、卫生条件差和营养不良等传播。 全球麻风研究领域，阻碍了消除麻风的进展。此外，更好的 为了取得进展，迫切需要早期诊断的监测战略和工具。我们的集成 一系列的目标试图通过使用最先进的血清学多重珠状试验(MBA)来填补这些空白 通过麻风融合的血清学反应评估麻风分枝杆菌的社区负担 蛋白质、LID-1和高分辨代谢组学(HRM)，以确定潜在的早期感染标志物。至 要做到这一点，我们将在全社区范围内对1,200名个人(3岁)进行调查，从 麻风高发城市检测抗LID-1抗体及其他 地方性非传染性疾病，如血吸虫病、弓形虫病和蛔虫病。结合这一化验结果 地理信息系统(GIS)将识别发病率和流行率的空间集群 以及感染的环境风险因素。抗LID-1抗体阳性和配对阴性者 控制组将参加一项为期3年的纵向研究(n=480)，以确定麻风传播的风险因素， 包括合并感染、营养不足以及与水、卫生设施和个人卫生条件差有关的因素 (洗涤)。我们将进行为期六个月的随访，以发现新的麻风病例或麻风反应 通过常规临床检查暴露于疾病中，并将包括免疫学检测(Th1，Th2， 和Th17细胞因子)，通过粪卵和寄生虫检查进行蠕虫检测，以及微量营养素检测。最后，我们的 第三个目标将使用高分辨率代谢组学(HRM)来识别内源性 与大量营养素相关的代谢物和与麻风杆菌相关的能量代谢可能导致 麻风早期诊断的生物标记物的鉴定。将执行人力资源管理以进行比较 无活动麻风的抗LID-1抗体阳性个体的代谢特征 小样本无症状抗-LID-1阴性对照，目的是检测潜在的生物标记物 与临床和亚临床麻风一致。人力资源管理将在任何世卫组织的随访期内重复 发展为麻风病，并在结束时为剩余的无症状个体比较基线代谢物 那些患上活跃麻风病的人和那些没有患上麻风病的人。总之，这个真正具有翻译性的项目将 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 确定和量化相关传播因素的补充、诊断和监测方法 消除贫穷是实施有针对性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.