Metabolomics : Official journal of the Metabolomic Society · 2025
Mycobacterium tuberculosis curli pili (MTP) facilitates pathogenicity by modulating oxidative phosphorylation and carbon flux during early infection of A549 epithelial cells.
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Naidoo Tarien J, Ashokcoomar Shinese, Truebody Barry, Mackenzie Jared S, Cumming Bridgette M, Steyn Adrie J C, Pillay Manormoney
Аннотация
BACKGROUND: The Mycobacterium tuberculosis (Mtb) curli pili (MTP) adhesin has been reported as a significant target for TB diagnostic and intervention strategies. The precise contribution of MTP in modulating oxidative phosphorylation (OXPHOS) and central carbon metabolism (CCM) within host epithelial cells is currently unknown.
OBJECTIVES: This study aimed to investigate the impact of MTP in whole cell bioenergetics during early stages of infection.
METHODS: Extracellular flux analysis was used to determine the role of MTP in modulating OXPHOS in A549 epithelial cells. 13C-metabolic flux analysis was performed on Mtb mtp proficient/deficient infected A549 epithelial cells to determine whether any specific changes in carbon flux through CCM are induced by the adhesin.
RESULTS: The absence of MTP led to an increase in OXPHOS in infected A549 cells, thereby increasing ATP synthesis. The Δmtp-infected A549 cells displayed a similar metabolic profile to the uninfected A549 cells. 13C-isotopomer metabolomic analysis of infected A549 cells suggested that MTP plays a role in decreasing glycolytic flux, enhancing flux through the pentose phosphate pathway (PPP), and modulating tricarboxylic acid (TCA) cycle intermediates by increasing flux through succinate.
CONCLUSIONS: The decreased basal respiration and flux through glycolysis and PPP of Mtb-infected A549 cells potentially decreased innate immune responses and production of signalling molecules to interact with immunocytes and activate adaptive immune responses. The similar metabolic profile of Δmtp-infected A549 cells and uninfected A549 cells suggests that the absence of the adhesin decreases virulence of Mtb. These findings substantiate MTP as an eminent biomarker for TB diagnostics/intervention strategies, and a novel target for vaccine development.
OBJECTIVES: This study aimed to investigate the impact of MTP in whole cell bioenergetics during early stages of infection.
METHODS: Extracellular flux analysis was used to determine the role of MTP in modulating OXPHOS in A549 epithelial cells. 13C-metabolic flux analysis was performed on Mtb mtp proficient/deficient infected A549 epithelial cells to determine whether any specific changes in carbon flux through CCM are induced by the adhesin.
RESULTS: The absence of MTP led to an increase in OXPHOS in infected A549 cells, thereby increasing ATP synthesis. The Δmtp-infected A549 cells displayed a similar metabolic profile to the uninfected A549 cells. 13C-isotopomer metabolomic analysis of infected A549 cells suggested that MTP plays a role in decreasing glycolytic flux, enhancing flux through the pentose phosphate pathway (PPP), and modulating tricarboxylic acid (TCA) cycle intermediates by increasing flux through succinate.
CONCLUSIONS: The decreased basal respiration and flux through glycolysis and PPP of Mtb-infected A549 cells potentially decreased innate immune responses and production of signalling molecules to interact with immunocytes and activate adaptive immune responses. The similar metabolic profile of Δmtp-infected A549 cells and uninfected A549 cells suggests that the absence of the adhesin decreases virulence of Mtb. These findings substantiate MTP as an eminent biomarker for TB diagnostics/intervention strategies, and a novel target for vaccine development.