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Artesunate Tolerance in Transgenic Plasmodium falciparumParasites Overexpressing a Tryptophan-Rich Protein
- Source :
- Antimicrobial Agents and Chemotherapy; March 2011, Vol. 55 Issue: 6 p2576-2584, 9p
- Publication Year :
- 2011
-
Abstract
- ABSTRACTDue to their rapid, potent action on young and mature intraerythrocytic stages, artemisinin derivatives are central to drug combination therapies for Plasmodium falciparummalaria. However, the evidence for emerging parasite resistance/tolerance to artemisinins in southeast Asia is of great concern. A better understanding of artemisinin-related drug activity and resistance mechanisms is urgently needed. A recent transcriptome study of parasites exposed to artesunate led us to identify a series of genes with modified levels of expression in the presence of the drug. The gene presenting the largest mRNA level increase, Pf10_0026(PArt), encoding a hypothetical protein of unknown function, was chosen for further study. Immunodetection with PArt-specific sera showed that artesunate induced a dose-dependent increase of the protein level. Bioinformatic analysis showed that PArtbelongs to a Plasmodium-specific gene family characterized by the presence of a tryptophan-rich domain with a novel hidden Markov model (HMM) profile. Gene disruption could not be achieved, suggesting an essential function. Transgenic parasites overexpressing PArt protein were generated and exhibited tolerance to a spike exposure to high doses of artesunate, with increased survival and reduced growth retardation compared to that of wild-type-treated controls. These data indicate the involvement of PArtin parasite defense mechanisms against artesunate. This is the first report of genetically manipulated parasites displaying a stable and reproducible decreased susceptibility to artesunate, providing new possibilities to investigate the parasite response to artemisinins.
Details
- Language :
- English
- ISSN :
- 00664804 and 10986596
- Volume :
- 55
- Issue :
- 6
- Database :
- Supplemental Index
- Journal :
- Antimicrobial Agents and Chemotherapy
- Publication Type :
- Periodical
- Accession number :
- ejs57155112
- Full Text :
- https://doi.org/10.1128/AAC.01409-10