Ornithine decarboxylase or gamma-glutamylcysteine synthetase overexpression protects Leishmania (Vianna) guyanensis against antimony
| Autor: | Maisa S. Fonseca, Bethânia V. Resende, Douglas de Souza Moreira, Ana Maria Murta Santi, Silvane M. F. Murta, Antônio P. Zoboli, Marcelo A. Comini |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Antimony
Leishmaniasis Mucocutaneous 0301 basic medicine Eflornithine genetic structures Glutamate-Cysteine Ligase Blotting Western 030106 microbiology Immunology Leishmania guyanensis Trypanothione Ornithine Decarboxylase Gene Expression Regulation Enzymologic Ornithine decarboxylase Inhibitory Concentration 50 03 medical and health sciences chemistry.chemical_compound medicine Animals Buthionine sulfoximine Enzyme Inhibitors Buthionine Sulfoximine biology fungi Neglected Diseases General Medicine Ornithine Decarboxylase Inhibitors Leishmania biology.organism_classification Recombinant Proteins 030104 developmental biology Infectious Diseases Biochemistry Ornithine Decarboxylase Inhibitor chemistry Cell culture Parasitology Rabbits medicine.drug |
| Zdroj: | Experimental Parasitology. 175:36-43 |
| ISSN: | 0014-4894 |
| DOI: | 10.1016/j.exppara.2017.02.001 |
| Popis: | Trypanosomatids present a unique mechanism for detoxification of peroxides that is dependent on trypanothione (bisglutathionylspermidine). Ornithine decarboxylase (ODC) and γ-glutamylcysteine synthetase (GSH1) produce molecules that are direct precursors of trypanothione. In this study, Leishmania guyanensis odc and gsh1 overexpressor cell lines were generated to investigate the contribution of these genes to the trivalent antimony (SbIII)-resistance phenotype. The ODC- or GSH1-overexpressors parasites presented an increase of two and four-fold in SbIII-resistance index, respectively, when compared with the wild-type line. Pharmacological inhibition of ODC and GSH1 with the specific inhibitors α-difluoromethylornithine (DFMO) and buthionine sulfoximine (BSO), respectively, increased the antileishmanial effect of SbIII in all cell lines. However, the ODC- and GSH1-overexpressor were still more resistant to SbIII than the parental cell line. Together, our data shows that modulation of ODC and GSH1 levels and activity is sufficient to affect L. guyanensis susceptibility to SbIII, and confirms a role of these genes in the SbIII-resistance phenotype. |
| Databáze: | OpenAIRE |
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