mTOR-associated Mitochondrial Energy Metabolism Limits Mycobacterium ESX-1-induced Cytotoxicity

Abstract Necrosis of macrophages in the tuberculous granuloma represents a major pathogenic event in tuberculosis. Through a zebrafish forward genetic screen, we identified the mTOR kinase, a master regulator of metabolism, as an early host resistance factor in tuberculosis. We found that mTOR protects macrophages from mycobacterium-induced death by enabling infection-induced increases in mitochondrial energy metabolism fueled by glycolysis. These metabolic adaptations were required to prevent mitochondrial damage and death caused specifically by the mycobacterial ESX-1 secretion system. Our finding that the host can effectively counter this early critical mycobacterial virulence mechanism simply by regulating energy metabolism may help explain why Mycobacterium tuberculosis, albeit humanity’s most lethal pathogen, only causes disease in a minority of infected individuals. This work was supported by a Wellcome Trust Principal Research Fellowship (103950/Z/14) and an NIH MERIT award (R37 AI054503) (L.R.).