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

Abstract

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.

• Authors: Ibeth Romero, Jair Téllez, Alvaro José Romanha, Mario Steindel, Edmundo Carlos Grisard
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 59 Issue 8 Pg. 4770-81 (Aug 2015) ISSN: 1098-6596 [Electronic] United States
• PMID: 26033728 (Publication Type: Journal Article)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• Antiprotozoal Agents
• Protozoan Proteins
• Antimony
• Hydrogen Peroxide
• Cysteine Synthase
• Cystathionine beta-Synthase

Topics

• Antimony (pharmacology)
• Antiprotozoal Agents (pharmacology)
• Cell Line
• Cystathionine beta-Synthase (genetics)
• Cysteine Synthase (genetics)
• Humans
• Hydrogen Peroxide (pharmacology)
• Leishmania braziliensis (drug effects, genetics)
• Leishmaniasis, Cutaneous (drug therapy, parasitology)
• Oxidative Stress (drug effects, physiology)
• Protozoan Proteins (genetics)
• Transcriptional Activation (drug effects, genetics)
• Trypanosoma rangeli (drug effects, genetics)
• Up-Regulation (drug effects, genetics)