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Mammalian target of Rapamycin inhibition and mycobacterial survival are uncoupled in murine macrophages

BACKGROUND: Autophagy is a cellular response to intracellular pathogens including mycobacteria and is induced by the direct inhibitors of mammalian target of Rapamycin (mTOR), a major negative regulator of autophagy. Autophagy induction by mTOR inhibition (mTOR dependent autophagy), through chemical...

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Autores principales: Zullo, Alfred J, Jurcic Smith, Kristen L, Lee, Sunhee
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937017/
https://www.ncbi.nlm.nih.gov/pubmed/24528777
http://dx.doi.org/10.1186/1471-2091-15-4
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author Zullo, Alfred J
Jurcic Smith, Kristen L
Lee, Sunhee
author_facet Zullo, Alfred J
Jurcic Smith, Kristen L
Lee, Sunhee
author_sort Zullo, Alfred J
collection PubMed
description BACKGROUND: Autophagy is a cellular response to intracellular pathogens including mycobacteria and is induced by the direct inhibitors of mammalian target of Rapamycin (mTOR), a major negative regulator of autophagy. Autophagy induction by mTOR inhibition (mTOR dependent autophagy), through chemical means or starvation, leads to mycobacterial killing in infected cells. However, previous work by our group has shown that mycobacterial infection of macrophages naturally induces both autophagy and mammalian target of Rapamycin (mTOR) activity (mTOR independent autophagy). In the current work, we further explore the relationship between mTOR activity and mycobacterial killing in macrophages. RESULTS: While low concentrations of the mTOR inhibitors, Rapamycin, Torin 1, and Torin 2, can effectively reduce or block mTOR activity in response to lipopolysaccharides (LPS) or mycobacteria, higher concentrations (10 uM) are required to observe Mycobacterium smegmatis killing. The growth of M. smegmatis was also inhibited by high concentrations of Rapamycin in LC3B and ATG5 deficient bone marrow derived macrophages, suggesting that non-autophagic mechanisms might contribute to killing at high doses. Since mycobacterial killing could be observed only at fairly high concentrations of the mTOR inhibitors, exceeding doses necessary to inhibit mTOR, we hypothesized that high doses of Rapamycin, the most commonly utilized mTOR inhibitor for inducing autophagic killing, may exert a direct bactericidal effect on the mycobacteria. Although a short-term treatment of mycobacteria with Rapamycin did not substantially affect mycobacterial growth, a long-term exposure to Rapamycin could impact mycobacterial growth in vitro in select species. CONCLUSIONS: This data, coupled with previous work from our laboratory, further indicates that autophagy induction by mTOR inhibition is an artificial means to increase mycobacterial killing and masks more relevant endogenous autophagic biochemistry that needs to be understood.
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spelling pubmed-39370172014-02-28 Mammalian target of Rapamycin inhibition and mycobacterial survival are uncoupled in murine macrophages Zullo, Alfred J Jurcic Smith, Kristen L Lee, Sunhee BMC Biochem Research Article BACKGROUND: Autophagy is a cellular response to intracellular pathogens including mycobacteria and is induced by the direct inhibitors of mammalian target of Rapamycin (mTOR), a major negative regulator of autophagy. Autophagy induction by mTOR inhibition (mTOR dependent autophagy), through chemical means or starvation, leads to mycobacterial killing in infected cells. However, previous work by our group has shown that mycobacterial infection of macrophages naturally induces both autophagy and mammalian target of Rapamycin (mTOR) activity (mTOR independent autophagy). In the current work, we further explore the relationship between mTOR activity and mycobacterial killing in macrophages. RESULTS: While low concentrations of the mTOR inhibitors, Rapamycin, Torin 1, and Torin 2, can effectively reduce or block mTOR activity in response to lipopolysaccharides (LPS) or mycobacteria, higher concentrations (10 uM) are required to observe Mycobacterium smegmatis killing. The growth of M. smegmatis was also inhibited by high concentrations of Rapamycin in LC3B and ATG5 deficient bone marrow derived macrophages, suggesting that non-autophagic mechanisms might contribute to killing at high doses. Since mycobacterial killing could be observed only at fairly high concentrations of the mTOR inhibitors, exceeding doses necessary to inhibit mTOR, we hypothesized that high doses of Rapamycin, the most commonly utilized mTOR inhibitor for inducing autophagic killing, may exert a direct bactericidal effect on the mycobacteria. Although a short-term treatment of mycobacteria with Rapamycin did not substantially affect mycobacterial growth, a long-term exposure to Rapamycin could impact mycobacterial growth in vitro in select species. CONCLUSIONS: This data, coupled with previous work from our laboratory, further indicates that autophagy induction by mTOR inhibition is an artificial means to increase mycobacterial killing and masks more relevant endogenous autophagic biochemistry that needs to be understood. BioMed Central 2014-02-14 /pmc/articles/PMC3937017/ /pubmed/24528777 http://dx.doi.org/10.1186/1471-2091-15-4 Text en Copyright © 2014 Zullo et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Zullo, Alfred J
Jurcic Smith, Kristen L
Lee, Sunhee
Mammalian target of Rapamycin inhibition and mycobacterial survival are uncoupled in murine macrophages
title Mammalian target of Rapamycin inhibition and mycobacterial survival are uncoupled in murine macrophages
title_full Mammalian target of Rapamycin inhibition and mycobacterial survival are uncoupled in murine macrophages
title_fullStr Mammalian target of Rapamycin inhibition and mycobacterial survival are uncoupled in murine macrophages
title_full_unstemmed Mammalian target of Rapamycin inhibition and mycobacterial survival are uncoupled in murine macrophages
title_short Mammalian target of Rapamycin inhibition and mycobacterial survival are uncoupled in murine macrophages
title_sort mammalian target of rapamycin inhibition and mycobacterial survival are uncoupled in murine macrophages
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937017/
https://www.ncbi.nlm.nih.gov/pubmed/24528777
http://dx.doi.org/10.1186/1471-2091-15-4
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