The goals of this research are to elucidate transcriptional networks that participate in the immune response to infection by Mycobacterium leprae (mLEP) and to devise therapeutic strategies that enhance the immune response by manipulating these networks. Many mLEP patients develop a self-limiting tuberculoid form of the disease (T-lep), in which an effective immune response is dependent on transcriptional networks in macrophages activated by Toll-like receptor ligands. Type II interferon (IFN-gamma), and IL-15. These stimuli drive the transcriptional activation of genes encoding key antimicrobial peptides and cytokines that promote a robust T helper 1 response. Vitamin D plays a major role in enhancing this response, as demonstrated by the increased susceptibility of vitamin D-deficient individuals to bacterial infection. In other patients, disseminated lepromatous (L-lep) lesions develop that appear to be caused, in part, by immune suppression by the Type I IFN, IFN-Beta. Projects 1, 2, and 4 of this application will focus on microbial stimuli that drive the mLEP response, proteins induced by IFN-gamma and IFN-Beta that either enhance or suppress the antimicrobial response, and vitamin D metabolic pathways as they pertain to antimicrobial immunity. In this Project, we hypothesize that elucidation and dissection of transcriptional networks activated by stimuli that either catalyze or suppress the immune response to mLEP infection will lead to key regulatory nodes and mechanisms that can be targeted by novel therapeutics strategies. This hypothesis is based on emerging excitement about the potential of chromatin and epigenetic regulators as therapeutic targets. We propose to: 1) use high-throughput sequencing analysis of transcriptional networks (RNAseq) to understand how multiple stimuli help shape the effective and ineffective immune responses that characterize T-lep and L-lep lesions; 2) elucidate the mechanism by which vitamin D suppresses the expression of important cytokines like IL-12 while promoting the expression of key antimicrobial peptides, towards the goal of uncoupling these activities in a therapeutic setting; 3) elucidate the mechanisms that distinguish the Type I and Type II IFN responses, towards the translational goal of converting the suppressive Type I response into an effective Type II response. These studies have considerable potential to translate basic knowledge of gene regulation circuitry into disease therapies and will provide knowledge of transcriptional networks that will be of great value to the goals of the entire CORT team and to other basic and translational researchers studying antimicrobial immunity.