Subversion of Schwann Cell Glucose Metabolism by Mycobacterium leprae

Abstract

Mycobacterium leprae, the intracellular etiological agent of leprosy, infects Schwann promoting irreversible physical disabilities and deformities. These cells are responsible for myelination and maintenance of axonal energy metabolism through export of metabolites, such as lactate and pyruvate. In the present work, we observed that infected Schwann cells increase glucose uptake with a concomitant increase in glucose-6-phosphate dehydrogenase (G6PDH) activity, the key enzyme of the oxidative pentose pathway. We also observed a mitochondria shutdown in infected cells and mitochondrial swelling in pure neural leprosy nerves. The classic Warburg effect described in macrophages infected by Mycobacterium avium was not observed in our model, which presented a drastic reduction in lactate generation and release by infected Schwann cells. This effect was followed by a decrease in lactate dehydrogenase isoform M (LDH-M) activity and an increase in cellular protection against hydrogen peroxide insult in a pentose phosphate pathway and GSH-dependent manner. M. leprae infection success was also dependent of the glutathione antioxidant system and its main reducing power source, the pentose pathway, as demonstrated by a 50 and 70% drop in intracellular viability after treatment with the GSH synthesis inhibitor buthionine sulfoximine, and aminonicotinamide (6-ANAM), an inhibitor of G6PDH 6-ANAM, respectively. We concluded that M. leprae could modulate host cell glucose metabolism to increase the cellular reducing power generation, facilitating glutathione regeneration and consequently free-radical control. The impact of this regulation in leprosy neuropathy is discussed.

GSMN-ML- a genome scale metabolic network reconstruction of the obligate human pathogenMycobacterium leprae

“…Our FBA analysis of GSMN-ML indicates that M. leprae is able to utilize both glucose and glycerol as carbon sources, consistent with evidence that glucose and/or glucose-derived metabolites were used as nutrients by M. leprae during in vivo growth [38], [49]. The finding may also be relevant to the observation that glucose metabolism of host Schwann cells is perturbed by M. leprae infection [49].…”

Innate Immune Responses in Leprosy

“…In addition to downregulating Schwann cell lineage transcripts and reactivating developmental genes, M. leprae induce a large numbers of immune-related genes comprising mostly innate immunity from the very early stage of Schwann cell infection and peaking in their expression when Schwann cells have changed their cell identity to pSLCs ( 29 ). A previous study demonstrated that M. leprae could modulate Schwann cell glucose metabolism to increase the generation of the reduction capacity and free-radical control ( 111 ), but the impact of these regulation in nerve damage needs to be more clarified.…”

Cytokine Levels in Neural Pain in Leprosy

“…Mycobacterium leprae alters mitochondrial glucose metabolism in Schwann cell (SC). This affects the complicated modulation of Schwann cell and axons, resulting in a reduction of axonal metabolism, demyelination, and loss of axons (6).…”