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.
['Stutz|Michael Dominic|MD|', 'Allison|Cody Charles|CC|', 'Ojaimi|Samar|S|', 'Preston|Simon Peter|SP|', 'Doerflinger|Marcel|M|', 'Arandjelovic|Philip|P|', 'Whitehead|Lachlan|L|', 'Bader|Stefanie M|SM|', 'Batey|Daniel|D|', 'Asselin-Labat|Marie-Liesse|ML|', 'Herold|Marco J|MJ|', 'Strasser|Andreas|A|', 'West|Nicholas P|NP|', 'Pellegrini|Marc|M|']
D000818:Animals D017209:Apoptosis D053181:Caspase 8 D002460:Cell Line D004151:Dipeptides D006801:Humans D007211:Indoles D008213:Lymphocyte Activation D008264:Macrophages D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D009169:Mycobacterium tuberculosis D009504:Neutrophils D011494:Protein Kinases D019253:Proto-Oncogene Proteins c-bcl-2 D013601:T-Lymphocytes D013844:Thiazoles D014397:Tuberculosis, Pulmonary
macrophages apoptosis Mycobacterium tuberculosis IAP antagonist caspase cell death pyroptosis