TY - JOUR
T1 - Mycobacterium tuberculosis-driven targeted recalibration of macrophage lipid homeostasis promotes the foamy phenotype
AU - Singh, Varshneya
AU - Jamwal, Shilpa
AU - Jain, Ritu
AU - Verma, Priyanka
AU - Gokhale, Rajesh
AU - Rao, Kanury V.S.
N1 - Funding Information:
This work was supported by a DBT grant to K.V.S.R. V.S. is the recipient of a SRF from CSIR. V.S., S.J., R.J., and P.V. conducted the research. R.G. participated in the data interpretation and lipid analysis. V.S. and K.V.S.R. designed the research and wrote the manuscript. K.V.S.R. supervised the project. The authors acknowledge A. Kumar and Z. Siddiqui for assistance with the mycobacterial cultures, S. Kumar for help with the mice experiments, N. Saquib for the mass spectrometric analysis, and A. Basu (NIV) for help with the electron microscopy. MPN was a gift from Sphaera Pharma. All animal experiments were conducted in the DBT-funded TACF facility at ICGEB.
PY - 2012/11/15
Y1 - 2012/11/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84869176200&partnerID=8YFLogxK
U2 - 10.1016/j.chom.2012.09.012
DO - 10.1016/j.chom.2012.09.012
M3 - Article
C2 - 23159056
AN - SCOPUS:84869176200
SN - 1931-3128
VL - 12
SP - 669
EP - 681
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 5
ER -