Implications of glutathione levels in the plasmodium berghei response to chloroquine and artemisinin

Joel Vega-Rodríguez, Rebecca Pastrana-Mena, Keila N. Crespo-Lladó, JoséG Ortiz, Iván Ferrer-Rodríguez, Adelfa E. Serrano

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Abstract

Malaria is one of the most devastating parasitic diseases worldwide. Plasmodium drug resistance remains a major challenge to malaria control and has led to the re-emergence of the disease. Chloroquine (CQ) and artemisinin (ART) are thought to exert their anti-malarial activity inducing cytotoxicity in the parasite by blocking heme degradation (for CQ) and increasing oxidative stress. Besides the contribution of the CQ resistance transporter (PfCRT) and the multidrug resistant gene (pfmdr), CQ resistance has also been associated with increased parasite glutathione (GSH) levels. ART resistance was recently shown to be associated with mutations in the K13-propeller protein. To analyze the role of GSH levels in CQ and ART resistance, we generated transgenic Plasmodium bergheiparasites either deficient in or overexpressing the gamma-glutamylcysteine synthetase gene (pbggcs) encoding the rate-limiting enzyme in GSH biosynthesis. These lines produce either lower (pbggcs-ko) or higher (pbggcs-oe) levels of GSH than wild type parasites. In addition, GSH levels were determined in P. berghei parasites resistant to CQ and mefloquine (MQ). Increased GSH levels were detected in both, CQ and MQ resistant parasites, when compared to the parental sensitive clone. Sensitivity to CQ and ART remained unaltered in both pgggcs-ko and pbggcs-oe parasiteswhen tested ina4daysdrugsuppressive assay. However, recrudescence assays after the parasites have been exposed to a sub-lethal dose of ART showed that parasites with low levels of GSH are more sensitive to ART treatment. These results suggest that GSH levels influence Plasmodium berghei response to ART treatment.

Original languageEnglish (US)
Article numbere0128212
JournalPLoS One
Volume10
Issue number5
DOIs
Publication statusPublished - May 26 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Vega-Rodríguez, J., Pastrana-Mena, R., Crespo-Lladó, K. N., Ortiz, J., Ferrer-Rodríguez, I., & Serrano, A. E. (2015). Implications of glutathione levels in the plasmodium berghei response to chloroquine and artemisinin. PLoS One, 10(5), [e0128212]. https://doi.org/10.1371/journal.pone.0128212