Inhibition of Fatty Acid Oxidation Promotes Macrophage Control of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>

ABSTRACT Macrophage activation involves metabolic reprogramming to support antimicrobial cellular functions. How these metabolic shifts influence the outcome of infection by intracellular pathogens remains incompletely understood. Mycobacterium tuberculosis (Mtb) modulates host metabolic pathways an...

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Autores principales:	Pallavi Chandra, Li He, Matthew Zimmerman, Guozhe Yang, Stefan Köster, Mireille Ouimet, Han Wang, Kathyrn J. Moore, Véronique Dartois, Joel D. Schilling, Jennifer A. Philips
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Mycobacterium tuberculosis NADPH oxidase fatty acid oxidation innate immunity macrophages mitochondrial metabolism Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9440bf7fd7254ee79c47ed8d7a264eb2
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spelling	oai:doaj.org-article:9440bf7fd7254ee79c47ed8d7a264eb22021-11-15T15:56:44ZInhibition of Fatty Acid Oxidation Promotes Macrophage Control of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>10.1128/mBio.01139-202150-7511https://doaj.org/article/9440bf7fd7254ee79c47ed8d7a264eb22020-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01139-20https://doaj.org/toc/2150-7511ABSTRACT Macrophage activation involves metabolic reprogramming to support antimicrobial cellular functions. How these metabolic shifts influence the outcome of infection by intracellular pathogens remains incompletely understood. Mycobacterium tuberculosis (Mtb) modulates host metabolic pathways and utilizes host nutrients, including cholesterol and fatty acids, to survive within macrophages. We found that intracellular growth of Mtb depends on host fatty acid catabolism: when host fatty acid β-oxidation (FAO) was blocked chemically with trimetazidine, a compound in clinical use, or genetically by deletion of the mitochondrial fatty acid transporter carnitine palmitoyltransferase 2 (CPT2), Mtb failed to grow in macrophages, and its growth was attenuated in mice. Mechanistic studies support a model in which inhibition of FAO generates mitochondrial reactive oxygen species, which enhance macrophage NADPH oxidase and xenophagy activity to better control Mtb infection. Thus, FAO inhibition promotes key antimicrobial functions of macrophages and overcomes immune evasion mechanisms of Mtb. IMPORTANCE Mycobacterium tuberculosis (Mtb) is the leading infectious disease killer worldwide. We discovered that intracellular Mtb fails to grow in macrophages in which fatty acid β-oxidation (FAO) is blocked. Macrophages treated with FAO inhibitors rapidly generate a burst of mitochondria-derived reactive oxygen species, which promotes NADPH oxidase recruitment and autophagy to limit the growth of Mtb. Furthermore, we demonstrate the ability of trimetazidine to reduce pathogen burden in mice infected with Mtb. These studies will add to the knowledge of how host metabolism modulates Mtb infection outcomes.Pallavi ChandraLi HeMatthew ZimmermanGuozhe YangStefan KösterMireille OuimetHan WangKathyrn J. MooreVéronique DartoisJoel D. SchillingJennifer A. PhilipsAmerican Society for MicrobiologyarticleMycobacterium tuberculosisNADPH oxidasefatty acid oxidationinnate immunitymacrophagesmitochondrial metabolismMicrobiologyQR1-502ENmBio, Vol 11, Iss 4 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Mycobacterium tuberculosis NADPH oxidase fatty acid oxidation innate immunity macrophages mitochondrial metabolism Microbiology QR1-502
spellingShingle	Mycobacterium tuberculosis NADPH oxidase fatty acid oxidation innate immunity macrophages mitochondrial metabolism Microbiology QR1-502 Pallavi Chandra Li He Matthew Zimmerman Guozhe Yang Stefan Köster Mireille Ouimet Han Wang Kathyrn J. Moore Véronique Dartois Joel D. Schilling Jennifer A. Philips Inhibition of Fatty Acid Oxidation Promotes Macrophage Control of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
description	ABSTRACT Macrophage activation involves metabolic reprogramming to support antimicrobial cellular functions. How these metabolic shifts influence the outcome of infection by intracellular pathogens remains incompletely understood. Mycobacterium tuberculosis (Mtb) modulates host metabolic pathways and utilizes host nutrients, including cholesterol and fatty acids, to survive within macrophages. We found that intracellular growth of Mtb depends on host fatty acid catabolism: when host fatty acid β-oxidation (FAO) was blocked chemically with trimetazidine, a compound in clinical use, or genetically by deletion of the mitochondrial fatty acid transporter carnitine palmitoyltransferase 2 (CPT2), Mtb failed to grow in macrophages, and its growth was attenuated in mice. Mechanistic studies support a model in which inhibition of FAO generates mitochondrial reactive oxygen species, which enhance macrophage NADPH oxidase and xenophagy activity to better control Mtb infection. Thus, FAO inhibition promotes key antimicrobial functions of macrophages and overcomes immune evasion mechanisms of Mtb. IMPORTANCE Mycobacterium tuberculosis (Mtb) is the leading infectious disease killer worldwide. We discovered that intracellular Mtb fails to grow in macrophages in which fatty acid β-oxidation (FAO) is blocked. Macrophages treated with FAO inhibitors rapidly generate a burst of mitochondria-derived reactive oxygen species, which promotes NADPH oxidase recruitment and autophagy to limit the growth of Mtb. Furthermore, we demonstrate the ability of trimetazidine to reduce pathogen burden in mice infected with Mtb. These studies will add to the knowledge of how host metabolism modulates Mtb infection outcomes.
format	article
author	Pallavi Chandra Li He Matthew Zimmerman Guozhe Yang Stefan Köster Mireille Ouimet Han Wang Kathyrn J. Moore Véronique Dartois Joel D. Schilling Jennifer A. Philips
author_facet	Pallavi Chandra Li He Matthew Zimmerman Guozhe Yang Stefan Köster Mireille Ouimet Han Wang Kathyrn J. Moore Véronique Dartois Joel D. Schilling Jennifer A. Philips
author_sort	Pallavi Chandra
title	Inhibition of Fatty Acid Oxidation Promotes Macrophage Control of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_short	Inhibition of Fatty Acid Oxidation Promotes Macrophage Control of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_full	Inhibition of Fatty Acid Oxidation Promotes Macrophage Control of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_fullStr	Inhibition of Fatty Acid Oxidation Promotes Macrophage Control of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_full_unstemmed	Inhibition of Fatty Acid Oxidation Promotes Macrophage Control of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_sort	inhibition of fatty acid oxidation promotes macrophage control of <named-content content-type="genus-species">mycobacterium tuberculosis</named-content>
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/9440bf7fd7254ee79c47ed8d7a264eb2
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Inhibition of Fatty Acid Oxidation Promotes Macrophage Control of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>

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