title: 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.
authors.affiliation: From the Laboratório de Microbiologia Celular.
authors.forename: Rychelle Clayde Affonso
authors.initials: RC
authors.lastname: Medeiros
authors.affiliation: From the Laboratório de Microbiologia Celular.
authors.forename: Karina do Carmo de Vasconcelos
authors.initials: KD
authors.lastname: Girardi
authors.affiliation: From the Laboratório de Microbiologia Celular.
authors.forename: Fernanda Karlla Luz
authors.initials: FK
authors.lastname: Cardoso
authors.affiliation: Hanseníase, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro-RJ.
authors.forename: Bruno de Siqueira
authors.initials: BS
authors.lastname: Mietto
authors.affiliation: Hanseníase, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro-RJ.
authors.forename: Thiago Gomes de Toledo
authors.initials: TG
authors.lastname: Pinto
authors.affiliation: the Laboratório de Enzimologia e controle do metabolismo and.
authors.forename: Lilian Sales
authors.initials: LS
authors.lastname: Gomez
authors.affiliation: Imunopatologia, Medical Science Faculty, Rio de Janeiro State University, Rio de Janeiro-RJ.
authors.forename: Luciana Silva
authors.initials: LS
authors.lastname: Rodrigues
authors.affiliation: From the Laboratório de Microbiologia Celular.
authors.forename: Mariana
authors.initials: M
authors.lastname: Gandini
authors.affiliation: the National Institute of Metrology, Quality and Technology INMETRO, Rio de Janeiro-RJ.
authors.forename: Julio Jablonski
authors.initials: JJ
authors.lastname: Amaral
authors.affiliation: Hanseníase, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro-RJ.
authors.forename: Sérgio Luiz Gomes
authors.initials: SL
authors.lastname: Antunes
authors.affiliation: Biologia Estrutural, and.
authors.forename: Suzana
authors.initials: S
authors.lastname: Corte-Real
authors.affiliation: the Department of Biology, Lauro de Souza Lima Institute, Bauru-SP, and.
authors.forename: Patricia Sammarco
authors.initials: PS
authors.lastname: Rosa
authors.affiliation: From the Laboratório de Microbiologia Celular.
authors.forename: Maria Cristina Vidal
authors.initials: MC
authors.lastname: Pessolani
authors.affiliation: Hanseníase, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro-RJ.
authors.forename: José Augusto da Costa
authors.initials: JA
authors.lastname: Nery
authors.affiliation: Hanseníase, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro-RJ.
authors.forename: Euzenir Nunes
authors.initials: EN
authors.lastname: Sarno
authors.affiliation: Hanseníase, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro-RJ.
authors.forename: Leonardo Ribeiro
authors.initials: LR
authors.lastname: Batista-Silva
authors.affiliation: the Laboratório de Enzimologia e controle do metabolismo and.
authors.forename: Mauro
authors.initials: M
authors.lastname: Sola-Penna
authors.affiliation: the Laboratório de Bioquímica de Resposta ao Estresse, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Marcus Fernandes
authors.initials: MF
authors.lastname: Oliveira
authors.affiliation: Hanseníase, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro-RJ.
authors.forename: Milton Ozório
authors.initials: MO
authors.lastname: Moraes
authors.affiliation: From the Laboratório de Microbiologia Celular, flavioalveslara2000@gmail.com.
authors.forename: Flavio Alves
authors.initials: FA
authors.lastname: Lara
mesh_terms: D002460:Cell Line; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism*; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism*; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D015441:Leprosy, Tuberculoid / Q000378:metabolism*; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D009166:Mycobacterium leprae / Q000378:metabolism*; D012583:Schwann Cells / Q000378:metabolism* / Q000382:microbiology
chemical_list: D019344:Lactic Acid; C042415:buthionine; D008715:Methionine; D005954:Glucosephosphate Dehydrogenase; D005947:Glucose
keywords: Leprosy; cell metabolism; glucose-6-phosphate dehydrogenase (G6PD or G6PDH); glutathione; host-target therapy; mitochondria; mycobacteria; neuron; oxidative stress; pentose phosphate pathway (PPP)