title: Intracellular Mycobacterium tuberculosis exploits host-derived fatty acids to limit metabolic stress.
abstract: Recent data indicate that the nutrients available to Mycobacterium tuberculosis (Mtb) inside its host cell are restricted in their diversity. Fatty acids and cholesterol appear more favored; however, their degradation can result in certain metabolic stresses. Their breakdown can generate propionyl-CoA, which gives rise to potentially toxic intermediates. Detoxification of propionyl-CoA relies on the activity of the methylcitrate cycle, the methylmalonyl pathway, or incorporation of the propionyl-CoA into methyl-branched lipids in the cell wall. The current work explores carbon flux through these pathways, focusing primarily on those pathways responsible for the incorporation of propionyl-CoA into virulence-associated cell wall lipids. Exploiting both genetic and biochemical rescue, we demonstrate that these metabolic pressures are experienced by Mtb inside its host macrophage and that the bacterium accesses host fatty acid stores. The metabolism of these host lipids expands the acetyl-CoA pool and alleviates the pressure from propionyl-CoA. These data have major implications for our appreciation of central metabolism of Mtb during the course of infection.
authors.affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14850, USA.
authors.forename: Wonsik
authors.initials: W
authors.lastname: Lee
authors.forename: Brian C
authors.initials: BC
authors.lastname: VanderVen
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Fahey
authors.forename: David G
authors.initials: DG
authors.lastname: Russell
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D054884:Host-Pathogen Interactions; D050356:Lipid Metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D010084:Oxidation-Reduction; D013229:Stearic Acids / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D000214:Acyl Coenzyme A; D001426:Bacterial Proteins; D005227:Fatty Acids; D013229:Stearic Acids; C009061:propionyl-coenzyme A; C031183:stearic acid; D000105:Acetyl Coenzyme A; D002784:Cholesterol