The parent studies for this grant address the molecular factors influencing expression of the surface protease GP63 of Leishmaniasis chagasi, and immune responses to L. chagasi infection in murine visceral leishmaniasis (VL), particularly the type 3 TGF-beta response. The FIRCA grant is proposed as an extension of the latter studies to understand the potential role that candidate host genetic factors may play in L. chagasi infection. The U.S. and foreign investigators have an ongoing collaboration to study the familial aggregation of VL in Natal, Brazil, having already identified and sampled 1401 individuals in 308 families. Also, they have evaluated potential environmental exposures using epidemiological strategies (i.e., showing lack of correlation of animal ownership and sand fly populations with VL and positive Montenegro (DTH to Leishmania antigen). The FIRCA will expand the sample to obtain more cases of VL, their families and neighborhood controls, and resample previously studied persons to characterize longitudinally the nature of delayed type hypersensitivity (DTH) to skin test response and Montenegro DTH in infected persons. They also have the unique opportunity to study potential changes in a previously sampled neighborhood which is no longer endemically exposed, due to pesticide control efforts. These subjects' peripheral blood mononuclear cells will also be immunologically phenotyped for response to L. chagasi antigens (ELISA) and cytokine gene expression, and the subjects' genotypes at candidate genes identified through the murine studies (IL-12R-beta-2, IL-10, Nramp1, and IL-4) will be performed. Familial aggregation, association studies, and model-free linkage studies will be conducted to determine whether genetic factors influence L. chagasi infection.
