Abstract Over 12 million people currently suffer from leishmaniasis, and ~2 million new cases occur each year, making it a major global health problem and a WHO classified neglected tropical disease. Visceral leishmaniasis (VL) is a life-threatening form of the disease caused by Leishmania donovani and Leishmania infantum and is characterized by parasite dissemination to the liver, spleen and bone marrow. Second to malaria, VL causes most deaths amongst parasitic diseases. The majority of VL cases caused by L. donovani are reported from East Africa, particularly Kenya, Sudan, South Sudan and Ethiopia. In Sudan, 40-50% of treated VL patients develop post kala azar dermal leishmaniasis (PKDL) which is characterized by proliferation of parasites in the skin leading to macular or nodular dermal lesions. PKDL self-resolves in the majority, but up to 20% of cases become chronic and non-healing. PKDL lesions have recently been implicated as a source of infection in sand flies. VL in eastern Africa is an epidemiologically and clinically diverse disease. in In East Africa, two distinct ecotypes of VL, the northern ecotype (NE-VL) in Northern Ethiopia and eastern Sudan and the southern ecotype (SE-VL) in southern Ethiopia, Kenya, Uganda and Somalia, have been identified based on genetic differences in parasites, and different sand fly vector species and ecological features. Phlebotomus martini (southern ecotype) have a micro-ecological preference for termite mounds (breeding /resting site); and P. orientalis (northern ecotype) depends on black cotton soil cracks. The disease phenotype and clinical outcomes also vary between the two ecotypes and within the northern ecotype. For example, PKDL is common in NE-VL but rare in SE-VL. Furthermore, although north Ethiopia and Sudan have genotypically similar parasites, PKDL is common in Sudan but rare in north Ethiopia. Likewise, there are differences in the therapeutic response to paramomycin and liposomal amphotericin as NE-VL responds poorly to treatment compared to SE-VL. Unlike Asia, VL in East Africa is targeted for control rather than elimination by WHO, partly due to significant knowledge gaps in ecoepidemiology, vector biology, and host and parasite factors driving transmission and pathogenesis. VL transmission is influenced by intrinsic factors such as vector competence, longevity and gut microbiota, and extrinsic factors including reservoir diversity, vector feeding preferences, and vector anthropophilicity, among others. Yet, how these factors promote VL transmission in Eastern Africa and elsewhere is poorly understood. To address these knowledge gaps, in this U01 project we propose to study the eco-epidemiology of VL at 4 sites in East Africa which are endemic for SE-VL (2 sites) or NE-VL (2 sites) and have different ecological and transmission features (Aim 1), determine the relative significance of factors that influence vector behavior and ecology as drivers of transmission (Aim 2), and identify ho...