Mechanisms of artemisinin resistance in the rodent malaria pathogen Plasmodium yoelii

Abstract

Artemisinin and its derivatives are important new antimalarials which are now used widely in Southeast Asia. Clinically relevant artemisinin resistance has not yet been reported but is likely to occur. In order to understand how the malaria parasite might become resistant to this drug, we studied artemisinin resistance in the murine malaria parasite Plasmodium yoelii. The artemisinin-resistant strain (ART), which is approximately fourfold less sensitive to artemisinin than the sensitive NS strain, accumulated 43% less radiolabeled drug in vitro (P < 0.01). Within the parasite, the drug appeared to react with the same parasite proteins in both strains. The translationally controlled tumor protein, one of the artemisinin target proteins, did not differ between the strains. No DNA sequence difference was found, but the resistant strain was found to express 2.5-fold-more protein than the sensitive strain (P < 0.01). Thus, the phenotype of artemisinin resistance in P. yoelii appears to be multifactorial.

FIG. 1

SDS gel autoradiogram of [³H]DHA-treated P. yoelii ART (artemisinin resistant [R]) and NS (artemisinin sensitive [S]).

FIG. 2

Alignment of TCTP sequences from P. yoelii and P. falciparum (GenBank accession number AA549873).

FIG. 3

Immunoblotting of P. yoelii gels using anti-TCTP. SDS (A) and IEF (B) gels were run on homogenates of P. yoelii strain NS, immunoblotted with anti-TCTP antibody, and visualized by enhanced chemiluminescence.