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.

Immunity and Immunopathology in the Tuberculous Granuloma

“…In vitro granuloma models suggest that foamy macrophages form through a host transcription-dependent process involving peroxisome proliferator g (PPARg) and testicular receptor 4 (TR4) and induced by mycobacterial oxygenated mycolic acids, which leads to the accumulation of lowdensity lipoprotein-derived lipids (Peyron et al 2008;Mahajan et al 2012). ESX-1-competent mycobacteria induce the foamy phenotype by diverting glycolitic metabolism toward ketone body synthesis and inducing the expression of the antilipolytic G-protein-coupled receptor GPR109A (Singh et al 2012). These macrophages are common in caseating granulomas, typically around the edges of the necrotic core, but rarely present in nonnecrotic lesions (Caceres et al 2009).…”

“…These macrophages are common in caseating granulomas, typically around the edges of the necrotic core, but rarely present in nonnecrotic lesions (Caceres et al 2009). Foamy macrophages are poorly bactericidal compared with their nonfoamy counterparts, attributed in part to increased M2-type macrophage activation and IL-10 production (Mahajan et al 2012) and impaired autophagy and lysosomal acidification (Singh et al 2012). In fact, recent work indicates that M1-type macrophage polarization inhibits foamy macrophage development.…”

Batf2/Irf1 Induces Inflammatory Responses in Classically Activated Macrophages, Lipopolysaccharides, and Mycobacterial Infection

“…Global analysis of Batf2 knockdown genes show wellcharacterized classical effectors such as Ccl11, Cxcl9, Ccr5, Niacr1, Il6ra, and Irg1 were downregulated after Batf2 knockdown. Interestingly, M. tuberculosis infection experiments using knockout mice from our list of Batf2-regulated genes, such as Nos2, Ccr5, Niacr1, Cxcr3, Irf1, and Stat1, showed either susceptible or resistant phenotypes to tuberculosis infection (49)(50)(51)(52)(53)(54)(55). Therefore, Batf2 may play an important role in immune response by possibly maintaining the balance in the inflammatory process.…”

Host-Directed Therapeutics for Tuberculosis: Can We Harness the Host?

“…1). Inhibition of GPR109A with mepenzolate bromide (MPN) led to increased killing of M. tuberculosis in THP1 cells and human peripheral blood monocyte-derived macrophages, as well as in murine in vivo studies (58). Lipid-sensing nuclear receptors: PPAR␥, LXR␣,␤, and TR4.…”