Leishmania of the (Viannia) subgenus are prevalent throughout Latin America. This subgenus causes self-limited cutaneous, chronic mucocutaneous and cutaneous disease, and asymptomatic infection. Although immune mediated hypersensitivity and the inflammatory response are hallmarks of human dermal disease caused by this L. Viannia, and may be therapeutically intervenable, the mechanisms involved in pathogenesis, parasite persistence and reactivation of disease are inadequately understood. Evidence of mixed Th1/Th2 responses throughout the spectrum of infection and disease (mucocutaneous, chronic and asymptomatic) indicates that disease pathogenesis involves distinct mechanisms from Old World dermatotrophic species. Understanding of the human immune response in pathogenesis, and persistence of infection has been constrained by:1) limited access to well defined, discrete clinical phenotypes;2) low resolution of methods applicable in human infection;3) lack of genetically defined, genetically and immunologically manipulatable experimental models. We will use high resolution technologies (RealTime PCR, microarray, cytometry, targeted gene deletion) clinically disparate, endemically exposed populations and experimentally infected BALB/c and knock out mice to understand the host response in chronic and recurrent disease, and parasite persistence.The ultimate goal of the research is to identify intervenable innate, inflammatory and adaptive processes of disease pathogenesis. Specific Aims are:1 )To determine if Th1/Th2 polarization occurs and is linked to the outcome of infection by L. Viannia;2) Define the frequency of low and high expression Mif alleles in individuals with chronic or recurrent leishmaniasis and asymptomatic infection, and determine if these alleles are associaed with outcome of infection;3) Determine the mechanisms that propiciate in vitro susceptibility of human macrophages to L. Viannia infection, and their relationship to clinical phenotype;4.) Use murine models of L. Viannia to dissect the host response.