Lactate oxidation facilitates growth of Mycobacterium tuberculosis in human macrophages

Abstract Mycobacterium tuberculosis (Mtb) uses alveolar macrophages as primary host cells during infection. In response to an infection, macrophages switch from pyruvate oxidation to reduction of pyruvate into lactate. Lactate might present an additional carbon substrate for Mtb. Here, we demonstrat...

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Autores principales:	Sandra Billig, Marie Schneefeld, Claudia Huber, Guntram A. Grassl, Wolfgang Eisenreich, Franz-Christoph Bange
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5a9ddd76b9534aa68d725bfbe922215f
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spelling	oai:doaj.org-article:5a9ddd76b9534aa68d725bfbe922215f2021-12-02T15:06:22ZLactate oxidation facilitates growth of Mycobacterium tuberculosis in human macrophages10.1038/s41598-017-05916-72045-2322https://doaj.org/article/5a9ddd76b9534aa68d725bfbe922215f2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05916-7https://doaj.org/toc/2045-2322Abstract Mycobacterium tuberculosis (Mtb) uses alveolar macrophages as primary host cells during infection. In response to an infection, macrophages switch from pyruvate oxidation to reduction of pyruvate into lactate. Lactate might present an additional carbon substrate for Mtb. Here, we demonstrate that Mtb can utilize L-lactate as sole carbon source for in vitro growth. Lactate conversion is strictly dependent on one of two potential L-lactate dehydrogenases. A knock-out mutant lacking lldD2 (Rv1872c) was unable to utilize L-lactate. In contrast, the lldD1 (Rv0694) knock-out strain was not affected in growth on lactate and retained full enzymatic activity. On the basis of labelling experiments using [U-13C3]-L-lactate as a tracer the efficient uptake of lactate by Mtb and its conversion into pyruvate could be demonstrated. Moreover, carbon flux from lactate into the TCA cycle, and through gluconeogenesis was observed. Gluconeogenesis during lactate consumption depended on the phosphoenolpyruvate carboxykinase, a key enzyme for intracellular survival, showing that lactate utilization requires essential metabolic pathways. We observed that the ΔlldD2 mutant was impaired in replication in human macrophages, indicating a critical role for lactate oxidation during intracellular growth.Sandra BilligMarie SchneefeldClaudia HuberGuntram A. GrasslWolfgang EisenreichFranz-Christoph BangeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sandra Billig Marie Schneefeld Claudia Huber Guntram A. Grassl Wolfgang Eisenreich Franz-Christoph Bange Lactate oxidation facilitates growth of Mycobacterium tuberculosis in human macrophages
description	Abstract Mycobacterium tuberculosis (Mtb) uses alveolar macrophages as primary host cells during infection. In response to an infection, macrophages switch from pyruvate oxidation to reduction of pyruvate into lactate. Lactate might present an additional carbon substrate for Mtb. Here, we demonstrate that Mtb can utilize L-lactate as sole carbon source for in vitro growth. Lactate conversion is strictly dependent on one of two potential L-lactate dehydrogenases. A knock-out mutant lacking lldD2 (Rv1872c) was unable to utilize L-lactate. In contrast, the lldD1 (Rv0694) knock-out strain was not affected in growth on lactate and retained full enzymatic activity. On the basis of labelling experiments using [U-13C3]-L-lactate as a tracer the efficient uptake of lactate by Mtb and its conversion into pyruvate could be demonstrated. Moreover, carbon flux from lactate into the TCA cycle, and through gluconeogenesis was observed. Gluconeogenesis during lactate consumption depended on the phosphoenolpyruvate carboxykinase, a key enzyme for intracellular survival, showing that lactate utilization requires essential metabolic pathways. We observed that the ΔlldD2 mutant was impaired in replication in human macrophages, indicating a critical role for lactate oxidation during intracellular growth.
format	article
author	Sandra Billig Marie Schneefeld Claudia Huber Guntram A. Grassl Wolfgang Eisenreich Franz-Christoph Bange
author_facet	Sandra Billig Marie Schneefeld Claudia Huber Guntram A. Grassl Wolfgang Eisenreich Franz-Christoph Bange
author_sort	Sandra Billig
title	Lactate oxidation facilitates growth of Mycobacterium tuberculosis in human macrophages
title_short	Lactate oxidation facilitates growth of Mycobacterium tuberculosis in human macrophages
title_full	Lactate oxidation facilitates growth of Mycobacterium tuberculosis in human macrophages
title_fullStr	Lactate oxidation facilitates growth of Mycobacterium tuberculosis in human macrophages
title_full_unstemmed	Lactate oxidation facilitates growth of Mycobacterium tuberculosis in human macrophages
title_sort	lactate oxidation facilitates growth of mycobacterium tuberculosis in human macrophages
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/5a9ddd76b9534aa68d725bfbe922215f
work_keys_str_mv	AT sandrabillig lactateoxidationfacilitatesgrowthofmycobacteriumtuberculosisinhumanmacrophages AT marieschneefeld lactateoxidationfacilitatesgrowthofmycobacteriumtuberculosisinhumanmacrophages AT claudiahuber lactateoxidationfacilitatesgrowthofmycobacteriumtuberculosisinhumanmacrophages AT guntramagrassl lactateoxidationfacilitatesgrowthofmycobacteriumtuberculosisinhumanmacrophages AT wolfgangeisenreich lactateoxidationfacilitatesgrowthofmycobacteriumtuberculosisinhumanmacrophages AT franzchristophbange lactateoxidationfacilitatesgrowthofmycobacteriumtuberculosisinhumanmacrophages
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Lactate oxidation facilitates growth of Mycobacterium tuberculosis in human macrophages

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