Mycobacterium tuberculosis (M.tb), etiologic agent of tuberculosis (TB), is still the leading cause of mortality by single bacterial infection worldwide. Annually, these air-borne bacilli kill almost 2 million people around the globe. M.tb is an extremely successful pathogen that have developed several strategies to neutralize the host immune defenses. One of significance is the block of phagosome maturation which results in survival and replication of M.tb inside macrophages. Autophagy is a cellular lysosomal degradative process which plays a fundamental role in immune responses to M.tb infection. Indeed, multiple reports show that extracellular inducers of autophagy promote phagosome maturation and killing of M.tb by macrophages. Furthermore, autophagy enhances BCG vaccine efficiency and antigen presentation. Although, M.tb succumbs to induced-autophagy, a recent study indicates that virulent M.tb can also modulate basal autophagy to survive intracellularly. Despite important progresses made in the research field of autophagy and mycobacterial infection, how M.tb regulates autophagy and its role in virulence remains largely unknown. To gain further insights into M.tb-autophagy interplay, we propose to decipherer the molecular mechanisms involved in autophagy regulation by M.tb using original, interdisciplinary and complementary approaches. We will (1) examine the correlation between virulence, pathogenicity of mycobacteria and autophagy modulation in human macrophages; (2) determine autophagy signaling pathways regulated by M.tb; (3) identify new M.tb factors that modulate autophagy. This project proposal will expand our understanding of the intricate relationship between M.tb and autophagy and its role in virulence which should help in the future design of innovative therapeutics for the fight against TB. Moreover, manipulating host autophagy might be one significant alternative for elimination of multi- and extensively-drug-resistant M.tb strains (M/XDR-TB).