title: Mycobacterium tuberculosis-driven targeted recalibration of macrophage lipid homeostasis promotes the foamy phenotype.
abstract: 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.
authors.affiliation: Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: Varshneya
authors.initials: V
authors.lastname: Singh
authors.forename: Shilpa
authors.initials: S
authors.lastname: Jamwal
authors.forename: Ritu
authors.initials: R
authors.lastname: Jain
authors.forename: Priyanka
authors.initials: P
authors.lastname: Verma
authors.forename: Rajesh
authors.initials: R
authors.lastname: Gokhale
authors.forename: Kanury V S
authors.initials: KV
authors.lastname: Rao
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000235:genetics; D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism*; D019898:Autocrine Communication; D001426:Bacterial Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006706:Homeostasis; D006801:Humans; D006885:Hydroxybutyrates / Q000378:metabolism; D007657:Ketone Bodies / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000382:microbiology; D050356:Lipid Metabolism; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000472:pathogenicity*; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D002785:Sterol O-Acyltransferase / Q000235:genetics; D000097587:Sterol O-Acyltransferase 2
chemical_list: D000101:Acetyl-CoA C-Acetyltransferase; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D006885:Hydroxybutyrates; D007657:Ketone Bodies; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2; C093276:ESAT-6 protein, Mycobacterium tuberculosis; C530636:HCAR2 protein, human; C506639:ACAT1 protein, human