Because of its endemic and chronic nature, schistosomiasis is easy to overlook relative to other more visible and publicized infectious diseases. It is a truly neglected and unconquered tropical disease, one for which we have consistently underestimated its health impact. Our means to control it are barely adequate and our expertise for dealing with it is limited and shrinking. Schistosomes undergo obligatory larval development in snails in which they produce human- infective cercariae in prodigious numbers. Control programs focus almost exclusively on treating people with the one widely available drug, praziquantel, yet drug-based control consistently fails to interrupt transmission because it ignores the central role of snails in supporting the schistosome life cycle. Over 90% of the world's victims of schistosomiasis live in sub-Saharan Africa, with one of the most prominent causal species being Schistosoma mansoni. This proposal focuses on the interactions between S. mansoni and its most common African snail host, Biomphalaria pfeifferi, as they co-occur in Kenya. We will provide new information regarding the role of snails in transmission, and how new methods of control could be developed to complement the existing uni-dimensional drug-centered programs. Throughout this project, the emphasis will be on B. pfeifferi snails taken straight from an active transmission site, and their interactions with S. mansoni miracidia derived directly from nearby infected children. Our four aims are united by the need to define the degree of compatibility that exists between wild snail and schistosome populations, and the factors that govern that level of compatibility. Building on work we have undertaken that has identified snail genes important in governing compatibility, we will attempt in the lab to alter expression of these genes in field- derived snails to learn if we can diminish compatibility. This would open the way for further studies in which snail compatibility might be manipulated to assist control efforts. Also, acknowledging that the impact of human infectious diseases can be reduced by ecological checks and balances, we will also explore the underappreciated role of natural enemies, including competing species of digenetic trematodes, in limiting S. mansoni's compatibility with, and prevalence in, B. pfeifferi. Finally, by applying modern techniques like microarray analysis and deep sequencing, we seek to define how snails respond to infection and to highlight physiological vulnerabilities of infected snails to enable us to better exploit thse weaknesses to selectively eliminate them in control efforts. This study is novel for its emphasis on applying modern molecular methods to wild snails and schistosomes in the African context, instead of dwelling on lab models. Also, this project is oriented around providing training for bot Kenyan and U.S. PhD students to maintain our expertise in an area that is suffering from a sharply dwindling number of investigators. Our work will ultimately favor development of more sustainable and successful means of schistosomiasis control in the part of the world where it is most urgently needed, tropical Africa.