DESCRIPTION: (provided by the applicant): Human infection with the protozoan Leishmania chagasi leads to a variety of outcomes ranging from asymptomatic infection to progressive and ultimately fatal visceral leishmaniasis. In addition many people living in endemic regions do not harbor evidence of L. chagasi infection despite their potential exposure. Several studies including our own have documented familial clustering of L. chagasi infection. This proposal will test the hypothesis that genetic factors predispose individuals to develop the different clinical outcomes after L. chagasi infection. Numerous cases of visceral leishmaniasis have occurred in neighborhoods outside the city of Natal in northeast Brazil over the past 10 years. In collaboration with Dr. Selma Jeronimo in Natal we have examined > 1400 individuals living in these endemic neighborhoods. Using a combination of historical and clinical information we determined whether they had asymptomatic or symptomatic L. chagasi infection, and their likelihood of exposure. We propose to use a genetic approach to identify factors associated with the different outcomes of human L. chagasi infection. Specific aims are: (1) To expand our database and bank of DNAs from individuals living in neighborhoods outside of Natal where L. chagasi infection is highly endemic. (2) To examine candidate genes associated with different phenotypic outcomes after L. chagasi exposure. (3) To perform a genome-wide scan and identify markers linked to phenotypecausing genes, using families selected with power studies. The scan will be followed by fine mapping and examination of further candidate susceptibility genes. During future years, we will extend these results to studies of antileishmanial immune responses in Brazilians with distinct genotypes and phenotypes. The goal of this project is to document the contribution of genetic factors to the clinical outcome of L. chagasi infection, and to identify specific alleles that influence human immune responses and thereby modify the course of disease.