Hurdles for controlling tuberculosis (TB) include the lack of a highly efficacious vaccine, prevention of infection, long drug treatment regimens, and killing dormant bacilli within macrophages. After close contact with an individual with pulmonary TB, most people develop latent Mtb infection (LTBI). However, some individuals are naturally resistant to infection (RSTRs). The mechanisms of resistance are unknown and may provide insight into novel therapeutic strategies. In a large TB household contact study in urban Uganda over the past 20 years, we found that ~9% of close adult household contacts remained persistently TST and Interferon-γ Release Assay (IGRA) negative during extended follow-up. To our knowledge, this large Ugandan cohort is unique with rigorous longitudinal clinical and epidemiologic data. Using gene-set enrichment and network analyses of transcriptional profiles of Mtb-infected peripheral blood-derived monocytes in the RSTR and LTBI groups, we found that the histone deacetylase (HDAC) gene family distinguishes RSTRs from LTBIs and may regulate resistance to Mtb infection. We performed a genome-wide linkage study in HIV-1 uninfected (HIV-) RSTRs in Uganda and discovered loci associated with this important clinical phenotype. In peripheral blood monocyte-derived and alveolar macrophages, HDAC inhibitor treatment decreased Mtb replication in comparison to untreated cells. Together, these data support our primary hypotheses that RSTRs have protective innate immune responses that are macrophage-dependent and partially HDAC-dependent. However, there are many gaps in our knowledge. First, the HDAC signature was network-based and we do not know if it is the major causal regulator of the RSTR phenotype. Second, HDACs are a family of 11 enzymes which modify chromatin and regulate transcription, cellular homeostasis, and the innate immune response to microbes. The details of which HDAC-dependent pathways are altered in RSTRs are unknown. Epigenetic and proteomic studies (including acetylation profiles) can address these gaps. Third, mechanisms of Mtb resistance in HIV+ individuals are completely unknown. Since HIV infection profoundly dysregulates T- cell responses to Mtb, HIV infected (HIV+) persons likely depend more on innate immunity to help control Mtb than HIV uninfected (HIV-) persons. In the R61 phase (Aim 1 and 2), we will use epigenetic, proteomic, and genetic approaches to discover candidate resistance genes and pathways that differ between RSTR and LTBI HIV+ and HIV- individuals. In the R33 phase (Aim 3), we will use cellular and in vivo approaches to discover mechanisms of resistance and small molecular inhibitors of these pathways that could be developed as host directed therapies.