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.