Inhibition of fatty acid oxidation promotes macrophage control of mycobacterium tuberculosis

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

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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. Mycobacte-rium 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 mac-rophage 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 in-hibitors 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.

Original languageEnglish
Article numbere01139-20
Pages (from-to)1-15
Number of pages15
JournalmBio
Volume11
Issue number4
DOIs
StatePublished - Aug 2020

Keywords

  • Fatty acid oxidation
  • Innate immunity
  • Macrophages
  • Mitochondrial metabolism
  • Mycobacterium tuberculosis
  • NADPH oxidase

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