TY - JOUR
T1 - Inhibition of fatty acid oxidation promotes macrophage control of mycobacterium tuberculosis
AU - Chandra, Pallavi
AU - He, Li
AU - Zimmerman, Matthew
AU - Yang, Guozhe
AU - Köster, Stefan
AU - Ouimet, Mireille
AU - Wang, Han
AU - Moore, Kathyrn J.
AU - Dartois, Véronique
AU - Schilling, Joel D.
AU - Philips, Jennifer A.
N1 - Funding Information:
We thank members of the Philips laboratory and Robert Mahon (NIH/NIAID) for critical reading of the manuscript. We thank Ronald E. Dolle (Washington University in St. Louis [WUSTL]) for help designing PK studies, Michael J. Wolfgang (Johns Hopkins University School of Medicine) for providing Cpt2fl/fl mice, and Jeffrey Cox (University of California, Berkeley) for providing the Rv-lux strain. We thank William Jacobs, Jr. (Albert Einstein College of Medicine) for the katG and esxA mutants. We thank the Alvin J. Siteman Cancer Center (WUSTL), Barnes-Jewish Hospital in St. Louis, MO, the Bursky Center for Human Immunology and Immunotherapy Programs Immunomonitoring Laboratory, and Diane Bender for the multiplexing immunoassay service. This work was supported by grants from the NIH (R21 AI128427, R01 AI130454), the Center for Drug Discovery (WUSTL), and LEAP Inventor Challenge Award (WUSTL) to J.A.P., NIH (R35 HL135799) to K.J.M., NIH (R01 DK11003404) to J.D.S., and the Potts Memorial Foundation to P.C. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant P30 CA091842. M.O. and S.K. did experiments demonstrating activity of etomoxir against intracellular Mtb, and P.C. performed all subsequent experiments. She had help with mice and MIC measurements from G.Y. and Seahorse experiments by L.H., M.Z., H.W., and V.D. measured TMZ concentrations from sera from infected mice. J.A.P. conceived the project and supervised the experiments with input from J.D.S. P.C. and J.A.P. wrote the manuscript; P.C., S.K., M.O., K.J.M., V.D., J.D.S., and J.A.P. edited the manuscript. We declare that we have no competing interests.
Funding Information:
This work was supported by grants from the NIH (R21 AI128427, R01 AI130454), the Center for Drug Discovery (WUSTL), and LEAP Inventor Challenge Award (WUSTL) to J.A.P., NIH (R35 HL135799) to K.J.M., NIH (R01 DK11003404) to J.D.S., and the Potts Memorial Foundation to P.C. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant P30 CA091842.
Publisher Copyright:
© 2020 Chandra et al.
PY - 2020/8
Y1 - 2020/8
N2 - 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.
AB - 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.
KW - Fatty acid oxidation
KW - Innate immunity
KW - Macrophages
KW - Mitochondrial metabolism
KW - Mycobacterium tuberculosis
KW - NADPH oxidase
UR - http://www.scopus.com/inward/record.url?scp=85087683778&partnerID=8YFLogxK
U2 - 10.1128/mBio.01139-20
DO - 10.1128/mBio.01139-20
M3 - Article
C2 - 32636249
AN - SCOPUS:85087683778
VL - 11
SP - 1
EP - 15
JO - mBio
JF - mBio
SN - 2161-2129
IS - 4
M1 - e01139-20
ER -