Macrophage and neutrophil death programs differentially confer resistance to tuberculosis

Apoptosis can potently defend against intracellular pathogens by directly killing microbes and eliminating their replicative niche. However, the reported ability of Mycobacterium tuberculosis to restrict apoptotic pathways in macrophages in vitro has led to apoptosis being dismissed as a host-protective process in tuberculosis despite a lack of in vivo evidence. Here we define crucial in vivo functions of the death receptor-mediated and BCL-2-regulated apoptosis pathways in mediating protection against tuberculosis by eliminating distinct populations of infected macrophages and neutrophils and priming T cell responses. We further show that apoptotic pathways can be targeted therapeutically with clinical-stage compounds that antagonize inhibitor of apoptosis (IAP) proteins to promote clearance of M. tuberculosis in mice. These findings reveal that any inhibition of apoptosis by M. tuberculosis is incomplete in vivo, advancing our understanding of host-protective responses to tuberculosis (TB) and revealing host pathways that may be targetable for treatment of disease. [Display omitted] •Control of M. tuberculosis is impaired in mice lacking extrinsic or intrinsic apoptosis•Caspase-8 mediates apoptosis of infected macrophages downstream of TNF•Intrinsic apoptosis functions primarily to eliminate neutrophils•Enhancing apoptosis with IAP antagonists promotes Mtb clearance in vivo Killing infected cells via apoptosis promotes elimination of intracellular pathogens, but this host defense was thought to be abrogated by Mycobacterium tuberculosis. Stutz et al. demonstrate that the apoptosis pathways promote tuberculosis control by clearing distinct populations of infected phagocytes and enhancing development of adaptive immune responses.