M. tuberculosis Secretory Protein ESAT-6 Induces Metabolic Flux Perturbations to Drive Foamy Macrophage Differentiation

Abstract

The Foamy Macrophage (FM) differentiation forms a major component of the host dependent survival axis of M. tuberculosis. The FM which are characterized by the intracellular accumulation of lipid bodies (LBs), ensure a privileged existence for the bacilli through ready provision of nutrients and by conferring protection against bactericidal pathways. The mycobacterial secretory protein ESAT-6 has been identified as the molecular mediator of the FM differentiation process although little is known about the mechanism through which it induces this process. In the present study, we show that ESAT-6 induces GLUT-1 mediated enhanced glucose uptake by macrophages which is coupled to metabolic flux perturbations in the glycolytic pathway caused by differential rates of reaction at several steps in the pathway. Two major changes identified were the simultaneous buildup of DHAP (for Triglyceride synthesis) and AcCoA (for synthesis of 3-HB, ligand for the anti-lipolytic GPR109A). We also show that part of the observed effects involve protein- protein interactions between ESAT-6 and the macrophage glycolytic enzymes, Enolase1 and Phosphoglycerate kinase1.

Advax4 delta inulin combination adjuvant together with ECMX, a fusion construct of four protective mTB antigens, induces a potent Th1 immune response and protects mice against Mycobacterium tuberculosis infection

“…36 ESAT-6 also induces an increase in macrophage glucose uptake and dysregulation of enzymes involved in triglyceride formation, which benefits mycobacterial nutrition and survival. 37 Hence, inclusion of ESAT-6 might explain the enhanced vaccine protection against Mtb seen with ECMX when compared to CMX vaccine.This study has a number of limitations. Due to the large number of animals needed for challenge testing, comparing the effectiveness of ECMX fusion protein against each individual antigen composing ECMX was not logistically possible.…”

A T4SS Effector Targets Host Cell Alpha-Enolase Contributing to Brucella abortus Intracellular Lifestyle

“…The first study demonstrates that hepatitis C virus (HCV) non-estructural protein NS5A interacts with cellular hexokinase 2 inducing an enhancement of the catalytic parameters of the enzyme, which might explain the aerobic glycolysis shift observed in HCV-infected cells (Ramière et al, 2014). The second report shows that Mycobacterium tuberculosis Early-Secreted Antigenic Target (ESAT-6), a virulence factor and a secretory protein playing important roles in pathogenesis, interacts with the macrophage glycolytic enzymes alpha-enolase and phosphoglycerate kinase 1 (Singh et al, 2015). …”

Evaluation of 5 Novel protein biomarkers for the rapid diagnosis of pulmonary and extra-pulmonary tuberculosis: preliminary results

“…The preparation of esat6 is described previously3132. The 38 kDa antigen was produced as N-terminal deca-histidine-tagged protein using T7 promoter-based expression system as described previously for hexa-histidine-tagged 38 kDa33.…”