Mycobacterium Tuberculosis is a highly effective pathogen infecting nearly a third of the world's population. An M. tuberculosis infection starts when droplets containing bacteria enter an individual's lungs. The first host cells to contact the bacteria are alveolar macrophages residing in the lung alveoli. These cells are usually in charge of phagocyting and killing pathogens; however, M. tuberculosis can survive and even replicate inside of them, leading to disease progression. In this thesis, we investigated how M. tuberculosis interacts with macrophages in two projects. In a first project, we used time-lapse microscopy and fluorescent reporters to study how diversity in the bacteria and the host cells influences the outcome of single-cell infections. By using M. tuberculosis strains expressing different fluorescent proteins, we showed that bacteria inside a same macrophage behave more similarly than bacteria in different cells, suggesting that some macrophages are more permissive to bacterial growth than others. Interestingly, these differences disappeared when inhibiting inducible nitric oxide synthase (iNOS), a known defense mechanism against M. tuberculosis. By using a macrophage reporter cell line for iNOS expression, we demonstrated that iNOS levels fluctuate in time in single cells, and that pre-existing heterogeneity in iNOS expression is linked to the control of intracellular M. tuberculosis by macrophages. As an infection with M. tuberculosis may initiate from a single bacterium internalized by a single macrophage, heterogeneity in the macrophage population could explain part of the variability observed in the outcome of Tuberculosis. Indeed, the level of iNOS a macrophage expresses when it is infected could influence how well it controls the initial infection and how the disease progresses. In a second project, we investigated the mechanisms leading to IL-1ß secretion in macrophages infected with M. tuberculosis. IL-1ß is a pro-inflammatory cytokine that plays a crucial role in host defense against M. tuberculosis by promoting inflammation and recruiting immune cells to the site of infection. As over-production of IL-1ß is deleterious to the host, its secretion is tightly regulated and requires the activation of a molecular platform called the inflammasome inside infected cells. Previous studies have demonstrated that IL-1ß secretion can be mediated by the NLRP3 and AIM2 inflammasomes upon M. tuberculosis infection. In this study, we demonstrated that IL-1ß can also be secreted upon activation of an alternative pathway, called the non-canonical inflammasome, in macrophages infected with M. tuberculosis. We showed that Caspase-11 (in mice), and Caspase-4 and Caspase-5 (in humans), the main proteins involved in non-canonical inflammasome activation, are activated in infected macrophages and contribute to IL-1ß secretion. Furthermore, we demonstrated that secreted IL-1ß can enhance the anti-mycobacterial properties of neighboring macrophages by promoting autophagy, a known defense mechanism against intracellular pathogens. By analyzing a publicly available sc-RNAseq dataset, we showed that Caspase-11 expression is induced in macrophages from the lungs of infected mice, suggesting a role for the control of M. tuberculosis infection in vivo. Our findings identify a novel mechanism for IL-1ß secretion in M. tuberculosis-infected cells and suggest a role for the non-canonical inflammasome in defense against mycobacteria.