PROJECT SUMMARY Tuberculosis (TB), caused by the intracellular pathogen Mycobacterium tuberculosis (Mtb), infects one-fourth of the world’s population. Majority of the infected individuals are latently infected (LTBI), of which 5-10% stand a risk of progressing to active TB disease (ATB) during their lifetime. There is limited knowledge about the precise mechanisms and pathways that mediate protective versus pathologic immunity during TB. Using RNA- sequencing analysis, we recently identified novel immune pathways upregulated during TB latency across species, namely Bone Morphogenetic Protein (BMP) signaling pathway. The BMP signaling pathway plays a prominent role in the regulation of lung development and adult lung homeostasis, and tissue repair following injury. However, the role of lung tissue repair and regeneration during TB latency is unexplored, and the specific role of the protective BMP-pathway in latent Mtb infection remains unknown. Moreover, our data suggests that lung tissue damage is being actively repaired in controllers during TB latency, without triggering a substantial inflammatory response. Therefore, we hypothesize that during TB latency, BMP signaling is upregulated mediating lung tissue repair, regeneration and Mtb control. This hypothesis will be addressed in the following two Specific Aims. In Specific Aim 1, we will determine the functional role of the BMP- pathway in Mtb control and TB reactivation. In Specific Aim 2, we will characterize the cellular mechanisms of BMP-pathway activation during TB latency. These studies can then pave the way for new strategies that will aid in the development of therapeutic interventions which can deter the progression from TB latency to TB disease.