mTOR-regulated mitochondrial metabolism limits mycobacterium-induced cytotoxicity.
Volume
185
Pagination
3720 - 3738.e13
DOI
10.1016/j.cell.2022.08.018
Journal
Cell
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Necrosis of macrophages in the granuloma, the hallmark immunological structure of tuberculosis, is a major pathogenic event that increases host susceptibility. 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 complex 1 protects macrophages from mycobacterium-induced death by enabling infection-induced increases in mitochondrial energy metabolism fueled by glycolysis. These metabolic adaptations are required to prevent mitochondrial damage and death caused by the secreted mycobacterial virulence determinant ESAT-6. Thus, the host can effectively counter this early critical mycobacterial virulence mechanism simply by regulating energy metabolism, thereby allowing pathogen-specific immune mechanisms time to develop. Our findings may explain why Mycobacterium tuberculosis, albeit humanity's most lethal pathogen, is successful in only a minority of infected individuals.
Authors
Pagán, AJ; Lee, LJ; Edwards-Hicks, J; Moens, CB; Tobin, DM; Busch-Nentwich, EM; Pearce, EL; Ramakrishnan, LCollections
- Biology [115]
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