The emergence of drug-resistant parasites is a serious threat faced by malaria control programs. Understanding the genetic basis\nof resistance is critical to the success of treatment and intervention strategies. A novel locus associated with antimalarial resistance,\nap2-mu (encoding the mu chain of the adaptor protein 2 [AP2] complex), was recently identified in studies on the rodent\nmalaria parasite Plasmodium chabaudi (pcap2-mu). Furthermore, analysis in Kenyan malaria patients of polymorphisms in the\nPlasmodium falciparum ap2-mu homologue, pfap2-mu, found evidence that differences in the amino acid encoded by codon 160\nare associated with enhanced parasite survival in vivo following combination treatments which included artemisinin derivatives.\nHere, we characterize the role of pfap2-mu in mediating the in vitro antimalarial drug response of P. falciparum by generating\ntransgenic parasites constitutively expressing codon 160 encoding either the wild-type Ser (Ser160) or the Asn mutant\n(160Asn) form of pfap2-mu. Transgenic parasites carrying the pfap2-mu 160Asn allele were significantly less sensitive to dihydroartemisinin\nusing a standard 48-h in vitro test, providing direct evidence of an altered parasite response to artemisinin. Our\ndata also provide evidence that pfap2-mu variants can modulate parasite sensitivity to quinine. No evidence was found that\npfap2-mu variants contribute to the slow-clearance phenotype exhibited by P. falciparum in Cambodian patients treated with\nartesunate monotherapy. These findings provide compelling evidence that pfap2-mu can modulate P. falciparum responses to\nmultiple drugs. We propose that this gene should be evaluated further as a potential molecular marker of antimalarial resistance.
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