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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 M. 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 (PPP) and glutathione reductase (GSR)-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 (BSO); 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.

More information

Type
Journal Article
Author
Medeiros RCA
Vasconcelos KGC
Cardoso FKL
Mieto BS
Pinto TGT
Gomez LS
Rodrigues LS
Gandini M
Amaral JJ
Antunes S
Côrte-Real S
Rosa P
Pessolani M
Costa Nery JA
Sarno E
Silva LRB
Sola-Penna M
Oliveira M
Moraes M
Lara F