The skin disease leprosy, caused by the Intracellular pathogen Mycobacterium leprae (mLEP), provides an extraordinary model to study cutaneous immune responses for at least three reasons: i) the disease is still a global health and economic burden, ii) the skin lesions are readily accessible for immunologic study; and, iii) the disease forms a spectrum in which the clinical manifestation correlate with the type of immune response to the pathogen. We propose to test the overall hypothesis that distinct IFNs differentially regulate human gene programs, including the vitamin D-dependent antimicrobial pathway, and thereby contribute to resistance vs. susceptibility to progressive infection in leprosy. The major thematic focus of this application is to understand the role of Type I vs. Type ll IFN pathways in regulatin cutaneous inflammation. The proposed model includes the identification of the mLEP antigens/ligands that induce Type I vs. Type II IFNs, the and downstream induction of antimicrobial activity and immune suppression (Project 1, Modlin) elucidation of the Type I vs. Type II IFN gene programs as related to the site of disease in leprosy and contributing to the distinct functional outcomes in the disease (Project 2, Cheng), understanding the gene clusters and transcriptional control of the IFN gene programs with relationship to the role of vitamin D in modulating these responses (Project 3, Smale); and, investigation of the role of IFNs in regulating vitamin D metabolism and downstream host defense mechanisms (Project 4, Adams), all through the assistance of a Bioinformatics Core (Pellegrini). The Administrative Core to facilitate research interactions between the projects through: i) research seminars, an Enrichment Program and meeting with an expert Advisory Board; ii), extend the research base through a Pilot and Feasibility Project Program; and leverage the resources and environment at UCLA including core facilities, the CTSI (CTSA) and training programs for medical and graduate students as well as those for postdoctoral fellows.