SUMMARY Schistosomiasis is a major neglected tropical disease, estimated to affect 240 million people worldwide, leading to loss of a minimum of 1.9 million disability-adjusted life years (DALYs) annually – 90% of this burden in sub- Saharan Africa. In East Africa, Uganda has a strong track-record of seminal studies and partnerships on schistosomiasis research. The Uganda Schistosomiasis Multidisciplinary Research Center (U-SMRC) will build on this solid foundation to develop a vibrant, Uganda-led, Uganda-based international schistosomiasis research network that fosters African capacity for transformative tropical medicine research. Uganda is highly endemic for Schistosoma mansoni (Sm). Intestinal schistosomiasis is universal in many villages around its Great Lakes and the River Nile. The Ministry of Health’s Vector Control Division (VCD), responsible for schistosomiasis control, has long been concerned by the high rates of severe schistosomal morbidity in the North-Western Lake Albert region (LA), compared to the Central and Eastern Lake Victoria region (LV), despite comparable transmission and programmes of praziquantel mass drug administration. In response to this concern, the U-SMRC’s core research goal is to understand the biological determinants of severe Sm- associated morbidity and to identify better strategies for its prevention and control. We hypothesise that key biological determinants of severe schistosomal morbidity occur at each stage of the parasite’s life cycle: in the human host, in the parasite, and in the snail host and its environment. To investigate this hypothesis, we will use two study designs: (i) cohorts of pre-school-age children (PSAC) in LA and LV, to explore the early evolution of immune responses that may lead to severe morbidity and (ii) an adult case control study to identify chronic exposures associated with severe disease. We will also collect parasite and snail samples from both settings, and develop a specimen archive for future studies. Our specific aims will be to Aim 1. Compare early-life immune responses to Sm exposure and infection between LA and LV and identify co-exposures that modulate Sm-specific immune responses and morbidity risk Aim 2. Establish a platform for local genetic surveillance of schistosome parasites in Uganda and determine whether there is a parasite genetic basis to differences in clinical outcomes in LA and LV Aim 3. Determine which population biological determinants of Biomphalaria spp. snails act as local epidemiological drivers of Sm, filtering its diversity within and between LA and LV ecosystems; and whether detection of environmental (e)DNA signatures from Biomphalaria and Sm can be used to better predict snail/parasite diversity at transmission sites and (re)infection risk within key demographic groups Data from each Aim will be used to develop a comprehensive, integrated model of the drivers of severe Sm- associated morbidity. This model will be further utilised to evaluate likely benefits of selected interventions, and to guide future policy on prevention and management.

NARRATIVE Intestinal schistosomiasis is a disease caused predominantly by Schistosoma mansoni and capable of causing notable sequelae including severe liver fibrosis, portal hypertension and often-fatal oesophageal bleeding. Its impact is most severe in poor, often hard-to-reach, communities in sub-Saharan Africa. The Uganda Schistosomiasis Multidisciplinary Research Center brings together international partners to build expertise and understanding of the underlying determinants of severe schistosomal morbidity, addressing each stage of the parasite’s life cycle; and to develop an integrated model for identifying appropriate interventions for prevention and management of this important disease.