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

使用新型血清学多重检测和高分辨率代谢组学检测确定与混合感染、不安全的洗涤和营养不良相关的麻风传播风险因素

• 批准号: 9890666
• 负责人: Jessica K. Fairley
• 金额: $ 15.6万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-16 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890666
• 关键词: 3 year old; Affect; Antibodies; Antigens; Area; Ascariasis; Bacteria; Biological Assay; Biological Markers; Brazil; Chimeric Proteins; Clinical; Communities; Complement; Data; Development; Diagnosis; Diagnostic; Disease; Early Diagnosis; Energy Metabolism; Enrollment; Environmental Risk Factor; Feces; Geographic Information Systems; Goals; Helminths; High Prevalence; Hygiene; Immunologics; Immunology procedure; In Vitro; Incidence; Individual; Infection; Intervention; Lead; Leprosy; Light; Longitudinal Studies; Longitudinal cohort; Macronutrients Nutrition; Malnutrition; Maps; Metabolic; Micronutrients; Monitor; Morbidity - disease rate; Municipalities; Mycobacterium leprae; Ovum; Parasites; Participant; Plasma; Poverty; Prevalence; Prospective cohort study; Public Health; Reaction; Research; Research Design; Resolution; Resources; Risk; Risk Factors; Sampling; Sanitation; Schistosomiasis; Series; Serological; Statistical Models; Strongyloidiasis; Surveys; Testing; Time; Water; clinical examination; co-infection; community burden; cytokine; diagnostic biomarker; follow-up; helminth infection; high risk; infection burden; innovation; metabolome; metabolomics; neglected tropical diseases; novel; novel diagnostics; nutrition; pathogen; potential biomarker; prospective; statistics; surveillance strategy; tool; transmission process

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.

项目概要 在世界许多地区，麻风病仍然是资金不足且未得到充分认识的重大发病原因 巴西是世界上发病率最高的国家之一，新发病例数位居第二 每年发生案件（2017 年为 22,940 起）。研究确定贫困相关因素对麻风病的影响 被忽视的热带病（NTD）、卫生条件差和营养不良等传播问题在 全球麻风病研究领域，阻碍了消除麻风病的进展。此外，更好 要取得进展，迫切需要早期诊断的监测策略和工具。我们的综合 一系列目标旨在通过使用最先进的血清学多重珠检测（MBA）来填补这些空白 通过麻风融合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) 来识别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 名个人（年龄 > 3 岁）进行一项全社区调查 麻风病高发城市检测抗 LID-1 抗体以及其他抗体的存在 地方性 NTD，例如血吸虫病、类圆线虫病和蛔虫病。合并该测定的结果 地理信息系统 (GIS) 将确定发病率和患病率的空间集群： 以及感染的环境危险因素。抗 LID-1 抗体阳性且匹配阴性者 对照者将参加一项为期 3 年的纵向研究（n=480），以确定麻风病传播的危险因素， 包括合并感染、营养缺乏以及与水、环境卫生和个人卫生条件差有关的因素 （洗）。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。 通过常规临床检查接触疾病，并将包括免疫测定（Th1、Th2、 和 Th17 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，我们的 第三个目标是使用高分辨率代谢组学 (HRM) 来识别内源性代谢特征 与麻风分枝杆菌相关的宏量营养素和能量代谢相关的代谢物可能导致 鉴定生物标志物以在最早阶段诊断麻风病。将进行 HRM 进行比较 无活动性麻风病的抗 LID-1 抗体阳性个体的代谢特征，该个体患有麻风病和 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。人力资源管理将在后续期间重复进行 发展麻风病，并在最后对剩余的无症状个体进行比较基线代谢组 患有活动性麻风病的人和没有患活动性麻风病的人。总之，这个真正的转化项目将 直接影响巴西这些地区的麻风病控制，并将成为第一个整合不同但但 互补的诊断和监测方法来识别和量化相关的传播因素 解决贫困问题，是实施有针对性的干预措施的关键一步。