mTOR-regulated mitochondrial metabolism limits mycobacterium-induced cytotoxicity

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 fac...

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Veröffentlicht in:Cell 2022-09, Vol.185 (20), p.3720-3738.e13
Hauptverfasser: Pagán, Antonio J, Lee, Lauren J, Edwards-Hicks, Joy, Moens, Cecilia B, Tobin, David M, Busch-Nentwich, Elisabeth M, Pearce, Erika L, Ramakrishnan, Lalita
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Sprache:eng
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Zusammenfassung: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.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2022.08.018