dc.contributor.author | Pagán, AJ | en_US |
dc.contributor.author | Lee, LJ | en_US |
dc.contributor.author | Edwards-Hicks, J | en_US |
dc.contributor.author | Moens, CB | en_US |
dc.contributor.author | Tobin, DM | en_US |
dc.contributor.author | Busch-Nentwich, EM | en_US |
dc.contributor.author | Pearce, EL | en_US |
dc.contributor.author | Ramakrishnan, L | en_US |
dc.date.accessioned | 2024-04-19T11:23:03Z | |
dc.date.available | 2022-08-16 | en_US |
dc.date.issued | 2022-09-29 | en_US |
dc.identifier.uri | https://qmro.qmul.ac.uk/xmlui/handle/123456789/96241 | |
dc.description.abstract | 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. | en_US |
dc.format.extent | 3720 - 3738.e13 | en_US |
dc.language | eng | en_US |
dc.language.iso | en | en_US |
dc.relation.ispartof | Cell | en_US |
dc.rights | This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. | |
dc.subject | ESAT-6 mitotoxicity | en_US |
dc.subject | Mycobacterium marinum | en_US |
dc.subject | Mycobacterium tuberculosis | en_US |
dc.subject | granuloma necrosis | en_US |
dc.subject | mTOR | en_US |
dc.subject | macrophage death | en_US |
dc.subject | mitochondrial metabolism | en_US |
dc.subject | oxidative phosphorylation | en_US |
dc.subject | tuberculosis | en_US |
dc.subject | zebrafish TB model | en_US |
dc.subject | Animals | en_US |
dc.subject | Mycobacterium marinum | en_US |
dc.subject | Mycobacterium tuberculosis | en_US |
dc.subject | TOR Serine-Threonine Kinases | en_US |
dc.subject | Tuberculosis | en_US |
dc.subject | Zebrafish | en_US |
dc.title | mTOR-regulated mitochondrial metabolism limits mycobacterium-induced cytotoxicity. | en_US |
dc.type | Article | |
dc.rights.holder | © 2022 The Authors. Published by Elsevier Inc. | |
dc.identifier.doi | 10.1016/j.cell.2022.08.018 | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/36103894 | en_US |
pubs.issue | 20 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published | en_US |
pubs.volume | 185 | en_US |
dcterms.dateAccepted | 2022-08-16 | en_US |
rioxxterms.funder | Default funder | en_US |
rioxxterms.identifier.project | Default project | en_US |