Mycobacterium tuberculosis-Driven Targeted Recalibration of Macrophage Lipid Homeostasis Promotes the Foamy Phenotype
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Upon infection, Mycobacterium tuberculosis (Mtb) metabolically alters the macrophage to create a niche that is ideally suited to its persistent lifestyle. Infected macrophages acquire a "foamy" phenotype characterized by the accumulation of lipid bodies (LBs), which serve as both a source of nutrients and a secure niche for the bacterium. While the functional significance of the foamy phenotype is appreciated, the biochemical pathways mediating this process are understudied. We found that Mtb induces the foamy phenotype via targeted manipulation of host cellular metabolism to divert the glycolytic pathway toward ketone body synthesis. This dysregulation enabled feedback activation of the anti-lipolytic G protein-coupled receptor GPR109A, leading to perturbations in lipid homeostasis and consequent accumulation of LBs in the macrophage. ESAT-6, a secreted Mtb virulence factor, mediates the enforcement of this feedback loop. Finally, we demonstrate that pharmacological targeting of pathways mediating this host-pathogen metabolic crosstalk provides a potential strategy for developing tuberculosis chemotherapy.
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M. tuberculosis diverts host metabolism from a glycolytic pathway toward ketone biosynthesis via the mycobacterial virulence factor ESAT-6.
“This is done by diversion of the host metabolism from a glycolytic pathway toward ketone biosynthesis, which is mediated by the mycobacterial virulence factor ESAT-6 (90).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [90]
Cites
Autophagy regulates lipid metabolism
Singh, R., Kaushik, S., Wang, Y., Xiang, Y., Novak, I., Komatsu, M., Tanaka, K., Cuervo, A. M., & Czaja, M. J. (2009) · Nature · doi:10.1038/nature07976 · Cited by 3,975 · see citing works
Regulation of hepatic fatty acid oxidation and ketone body production
McGarry, J. D., & Foster, D. W. (1980) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.49.070180.002143 · Cited by 1,460 · see citing works
Molecular analysis of genetic differences between Mycobacterium bovis BCG and virulent M. bovis
Mahairas, G. G., Sabo, P. J., Hickey, M. J., Singh, D. C., & Stover, C. K. (1996) · Journal of Bacteriology · doi:10.1128/jb.178.5.1274-1282.1996 · Cited by 1,103 · see citing works
Brasaemle, D. (2007) · Journal of Lipid Research · doi:10.1194/jlr.r700014-jlr200 · Cited by 997 · see citing works
Trends in the exploitation of novel drug targets
Rask-Andersen, M., Almén, M. S., & Schiöth, H. B. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3478 · Cited by 853 · see citing works
Foamy macrophages and the progression of the human tuberculosis granuloma
Russell, D. G., Cardona, P.-J., Kim, M., Allain‐Maillet, S., & Altare, F. (2009) · Nature Immunology · doi:10.1038/ni.1781 · Cited by 822 · see citing works
PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect
Tunaru, S., Kero, J. T., Schaub, A., Wufka, C., Blaukat, A., Pfeffer, K., & Offermanns, S. (2003) · Nature Medicine · doi:10.1038/nm824 · Cited by 794 · see citing works
Peyron, P., Vaubourgeix, J., Poquet, Y., Levillain, F., Botanch, C., Bardou, F., Daffé, M., Emile, J.-F., Marchou, B., Cardona, P.-J., et al. (2008) · PLoS Pathogens · doi:10.1371/journal.ppat.1000204 · Cited by 751 · see citing works
(d)-β-Hydroxybutyrate Inhibits Adipocyte Lipolysis via the Nicotinic Acid Receptor PUMA-G
Taggart, A. K. P., Kero, J. T., Gan, X., Cai, T., Cheng, K., Ippolito, M. C., Ren, N., Kaplan, R. A., Wu, K., Wu, T.-J., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.c500213200 · Cited by 651 · see citing works
Daniel, J., Maamar, H., Deb, C., Sirakova, T., & Kolattukudy, P. (2011) · PLoS Pathogens · doi:10.1371/journal.ppat.1002093 · Cited by 595 · see citing works
Deletion of RD1 from<i>Mycobacterium tuberculosis</i>Mimics Bacille Calmette‐Guérin Attenuation
Lewis, K. N., Liao, R., Guinn, K. M., Hickey, M. J., Smith, S., Behr, M. A., & Sherman, D. R. (2003) · The Journal of Infectious Diseases · doi:10.1086/345862 · Cited by 588 · see citing works
Sørensen, A. L., Nagai, S., Houen, G., Andersen, P., & Andersen, A. B. (1995) · Infection and Immunity · doi:10.1128/iai.63.5.1710-1717.1995 · Cited by 586 · see citing works
Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry
Fukao, T., Lopaschuk, G. D., & Mitchell, G. A. (2004) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2003.11.001 · Cited by 395 · see citing works
Pathak, S. K., Basu, S., Basu, K. K., Banerjee, A., Pathak, S., Bhattacharyya, A., Kaisho, T., Kundu, M., & Basu, J. (2007) · Nature Immunology · doi:10.1038/ni1468 · Cited by 369 · see citing works
Kumar, D., Nath, L., Kamal, M. A., Varshney, A., Jain, A., Singh, S., & Rao, K. V. S. (2010) · Cell · doi:10.1016/j.cell.2010.02.012 · Cited by 345 · see citing works
Self-citationShin, D.-M., Jeon, B., Lee, H., Jin, H. S., Yuk, J., Song, C., Lee, S. H., Lee, Z.-W., Cho, S.-N., Kim, J., et al. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1001230 · Cited by 337 · see citing works
Bowdish, D. M. E., Sakamoto, K., Kim, M., Klaas, M., Mukhopadhyay, S., Leifer, C. A., Tryggvason, K., Gordon, S., & Russell, D. G. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000474 · Cited by 320 · see citing works
Pathak, S. K., Basu, S., Basu, K. K., Banerjee, A., Pathak, S., Bhattacharyya, A., Kaisho, T., Kundu, M., & Basu, J. (2015) · Nature Immunology · doi:10.1038/ni0315-326b · Cited by 310 · see citing works
D’Avila, H., Melo, R. C. N., Parreira, G. G., Werneck-Barroso, E., Castro-Faria-Neto, H. C., & Bozza, P. T. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.5.3087 · Cited by 289 · see citing works
Control of M. tuberculosis ESAT-6 Secretion and Specific T Cell Recognition by PhoP
Frigui, W., Bottai, D., Majlessi, L., Monot, M., Josselin, E., Brodin, P. M., Garnier, T., Gicquel, B., Martı́n, C., Leclerc, C., et al. (2008) · PLoS Pathogens · doi:10.1371/journal.ppat.0040033 · Cited by 283 · see citing works
The Central Role of Perilipin A in Lipid Metabolism and Adipocyte Lipolysis
Tansey, J. T., Sztalryd, C., Hlavin, E. M., Kimmel, A. R., & Londos, C. (2004) · IUBMB Life · doi:10.1080/15216540400009968 · Cited by 275 · see citing works
GPR109A, GPR109B and GPR81, a family of hydroxy-carboxylic acid receptors
Ahmed, K., Tunaru, S., & Offermanns, S. (2009) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2009.09.001 · Cited by 247 · see citing works
Cyclic AMP intoxication of macrophages by a Mycobacterium tuberculosis adenylate cyclase
Agarwal, N., Lamichhane, G., Gupta, R., Nolan, S. T., & Bishai, W. R. (2009) · Nature · doi:10.1038/nature08123 · Cited by 230 · see citing works
Wieland, O. H., Patzelt, C., & Löffler, G. (1972) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1972.tb01783.x · Cited by 198 · see citing works
Mycobacterium tuberculosis Wears What It Eats
Russell, D. G., VanderVen, B. C., Lee, W., Abramovitch, R. B., Kim, M., Homolka, S., Niemann, S., & Rohde, K. H. (2010) · Cell Host & Microbe · doi:10.1016/j.chom.2010.06.002 · Cited by 194 · see citing works
Pathology of postprimary tuberculosis in humans and mice: Contradiction of long-held beliefs
Hunter, R. L., Jagannath, C., & Actor, J. K. (2007) · Tuberculosis · doi:10.1016/j.tube.2006.11.003 · Cited by 180 · see citing works
The nicotinic acid receptor GPR109A (HM74A or PUMA-G) as a new therapeutic target
Offermanns, S. (2006) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2006.05.008 · Cited by 179 · see citing works
Krause, B., Anderson, M., Bisgaier, C. L., et al. (1993) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)40755-2 · Cited by 148 · see citing works
SIESS, E. A., KIENTSCH-ENGEL, R. I., & WIELAND, O. H. (1982) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1982.tb05814.x · Cited by 45 · see citing works
Xu, F. Y., Taylor, W. A., Hurd, J. A., & Hatch, G. M. (2003) · Journal of Lipid Research · doi:10.1194/jlr.m200335-jlr200 · Cited by 41 · see citing works
ESAT-6 and CFP-10: What Is the Diagnosis?
van Pittius, N. C. G., Warren, R. M., & van Helden, P. D. (2002) · Infection and Immunity · doi:10.1128/iai.70.11.6509-6511.2002 · Cited by 41 · see citing works
Conversion of pyruvate into ketone bodies in rat hepatocyte suspensions
Battersby, C., Alberti, K. G. M. M., & Agius, L. (1985) · Biochemical Journal · doi:10.1042/bj2310565 · Cited by 5 · see citing works
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Macrophage defense mechanisms against intracellular bacteria
Weiss, G., & Schaible, U. E. (2015) · Immunological Reviews · doi:10.1111/imr.12266 · Cited by 989 · see citing works
Dietary gut microbial metabolites, short-chain fatty acids, and host metabolic regulation
Kasubuchi, M., Hasegawa, S., Hiramatsu, T., Ichimura, A., & Kimura, I. (2015) · Nutrients · doi:10.3390/nu7042839 · Cited by 904 · see citing works
Stanley, S. A., Barczak, A. K., Silvis, M. R., Luo, S. S., Sogi, K., Vokes, M., Bray, M.-A., Carpenter, A. E., Moore, C. B., Siddiqi, N., et al. (2014) · PLoS Pathogens · doi:10.1371/journal.ppat.1003946 · Cited by 251 · see citing works
Cutting Edge: Vitamin D Regulates Lipid Metabolism in <i>Mycobacterium tuberculosis</i> Infection
Salamon, H., Bruiners, N., Lakehal, K., Shi, L., Ravi, J., Yamaguchi, K. D., Pine, R., & Gennaro, M. L. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1400736 · Cited by 99 · see citing works
Exploitation of host lipids by bacteria
Vromman, F., & Subtil, A. (2014) · Current Opinion in Microbiology · doi:10.1016/j.mib.2013.11.003 · Cited by 42 · see citing works
- Authors
- Singh, V., Jamwal, S., Jain, R., Verma, P., Gokhale, R., & Rao, K. V. S.
- Affiliations
- International Centre for Genetic Engineering and Biotechnology (IN)
- National Institute of Immunology (IN)
- Institute of Genomics and Integrative Biology (IN)
- Corresponding author
- Rao, Kanury V.S.
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2012-11
- Volume
- 12
- Issue
- 5
- Pages
- 669-681
- ISSN
- 1931-3128 (ISSN-L)
- OpenAlex
- W1978993402
- Cited by
- 295
- References
- 32
- Citations by year
- 2026: 11 · 2025: 26 · 2024: 17 · 2023: 22 · 2022: 16 · 2021: 27 · 2020: 25 · 2019: 24 · 2018: 19 · 2017: 26 · 2016: 29 · 2015: 24 · 2014: 12 · 2013: 15 · 2012: 2
- FWCI
- 11.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Host & Microbe (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Department of Biotechnology, Ministry of Science and Technology, India
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- Mycobacterium tuberculosis, tuberculosis, lipid droplets, foam cells, ketone body synthesis, glycolysis, GPR109A, ESAT-6, tuberculosis chemotherapy
- MeSH terms
- Sterol O-Acyltransferase 2, Acetyl-CoA C-Acetyltransferase, Animals, Antigens, Bacterial, Bacterial Proteins, Sterol O-Acyltransferase, Female, Homeostasis, Humans, Hydroxybutyrates, Ketone Bodies, Leukocytes, Mononuclear, Macrophages, Mice, Inbred BALB C, Mycobacterium tuberculosis, Phenotype, Receptors, Nicotinic, Autocrine Communication, Receptors, G-Protein-Coupled, Cell Line, Tumor, Lipid Metabolism, Mice
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