Upregulation of Cysteine Synthase and Cystathionine β-Synthase Contributes to Leishmania braziliensis Survival under Oxidative Stress

Cysteine metabolism is considered essential for the crucial maintenance of a reducing environment in trypanosomatids due to its importance as a precursor of trypanothione biosynthesis. Expression, activity, functional rescue, and overexpression of cysteine synthase (CS) and cystathionine β-synthase...

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Bibliographic Details
Published in:Antimicrobial agents and chemotherapy 2015-08, Vol.59 (8), p.4770-4781
Main Authors: Romero, Ibeth, Téllez, Jair, Romanha, Alvaro José, Steindel, Mario, Grisard, Edmundo Carlos
Format: Article
Language:English
Subjects:
Antimony - pharmacology
Antiprotozoal Agents - pharmacology
Cell Line
Cystathionine beta-Synthase
Cystathionine beta-Synthase - genetics
Cysteine Synthase
Cysteine Synthase - genetics
Humans
Hydrogen Peroxide - pharmacology
Leishmania braziliensis
Leishmania braziliensis - drug effects
Leishmania braziliensis - genetics
Leishmaniasis, Cutaneous - drug therapy
Leishmaniasis, Cutaneous - parasitology
Mechanisms of Resistance
Oxidative Stress
Oxidative Stress - drug effects
Oxidative Stress - physiology
Protozoan Proteins
Protozoan Proteins - genetics
Transcriptional Activation - drug effects
Transcriptional Activation - genetics
Trypanosoma
Trypanosoma rangeli
Trypanosoma rangeli - drug effects
Trypanosoma rangeli - genetics
Up-Regulation
Up-Regulation - drug effects
Up-Regulation - genetics
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Summary:Cysteine metabolism is considered essential for the crucial maintenance of a reducing environment in trypanosomatids due to its importance as a precursor of trypanothione biosynthesis. Expression, activity, functional rescue, and overexpression of cysteine synthase (CS) and cystathionine β-synthase (CβS) were evaluated in Leishmania braziliensis promastigotes and intracellular amastigotes under in vitro stress conditions induced by hydrogen peroxide (H2O2), S-nitroso-N-acetylpenicillamine, or antimonial compounds. Our results demonstrate a stage-specific increase in the levels of protein expression and activity of L. braziliensis CS (LbrCS) and L. braziliensis CβS (LbrCβS), resulting in an increment of total thiol levels in response to both oxidative and nitrosative stress. The rescue of the CS activity in Trypanosoma rangeli, a trypanosome that does not perform cysteine biosynthesis de novo, resulted in increased rates of survival of epimastigotes expressing the LbrCS under stress conditions compared to those of wild-type parasites. We also found that the ability of L. braziliensis promastigotes and amastigotes overexpressing LbrCS and LbrCβS to resist oxidative stress was significantly enhanced compared to that of nontransfected cells, resulting in a phenotype far more resistant to treatment with the pentavalent form of Sb in vitro. In conclusion, the upregulation of protein expression and increment of the levels of LbrCS and LbrCβS activity alter parasite resistance to antimonials and may influence the efficacy of antimony treatment of New World leishmaniasis.
ISSN:0066-4804
1098-6596
DOI:10.1128/AAC.04880-14