Despite the discovery of Mycobacterium tuberculosis (Mtb) over 100 years ago and the availability of effective drugs for over 60 years, there remain formidable hurdles for controlling tuberculosis (TB) disease including the lack of a highly efficacious vaccine, long drug treatment regimens, prevention of infection, and killing dormant bacilli within macrophages. After close contact with a person 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-gamma 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 genome-wide profiling of mRNA isolated from Mtb-infected peripheral blood- derived monocytes, we compared transcriptional signatures 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. HDACs regulate transcription and some family members mediate the innate immune response to microbes. We also found polymorphisms in HDAC1 that are associated with resistance to infection. In peripheral blood monocyte-derived and alveolar macrophages, HDAC inhibitor treatment decreased Mtb replication in comparison to untreated cells. These findings support the concept that RSTRs have protective innate immune responses that are monocyte-dependent. However, several critical questions need to be addressed including elucidation of the molecular and genetic mechanisms of HDAC-mediated control of Mtb replication in macrophages and clinical resistance to Mtb infection. In addition, the role of alveolar macrophages in regulating HDAC-mediated immune responses is poorly understood. We hypothesize that HDACs mediate resistance to infection by inhibiting Mtb replication through transcriptional regulation of anti- microbial pathways. Characterization of HDAC-dependent immune responses will enable identification of natural resistance mechanisms to Mtb infection. The latter will provide new insight into our understanding of TB pathogenesis, point to novel approaches to TB vaccine and drug development, and identify biomarkers of resistance to and/or clearance of Mtb infection. The research aims will be integrated with a mentoring strategy for mentees that fosters development of patient-oriented research with a pathway to independence.