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<jats:title>ABSTRACT</jats:title><jats:p>The emergence of drug-resistant parasites is a serious threat faced by malaria control programs. Understanding the genetic basis of resistance is critical to the success of treatment and intervention strategies. A novel locus associated with antimalarial resistance,<jats:italic>ap2-mu</jats:italic>(encoding the mu chain of the adaptor protein 2 [AP2] complex), was recently identified in studies on the rodent malaria parasite<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Plasmodium chabaudi</jats:named-content>(<jats:italic>pcap2-mu</jats:italic>). Furthermore, analysis in Kenyan malaria patients of polymorphisms in the<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Plasmodium falciparum</jats:named-content><jats:italic>ap2-mu</jats:italic>homologue,<jats:italic>pfap2-mu</jats:italic>, found evidence that differences in the amino acid encoded by codon 160 are associated with enhanced parasite survival<jats:italic>in vivo</jats:italic>following combination treatments which included artemisinin derivatives. Here, we characterize the role of<jats:italic>pfap2-mu</jats:italic>in mediating the<jats:italic>in vitro</jats:italic>antimalarial drug response of<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content>by generating transgenic parasites constitutively expressing codon 160 encoding either the wild-type Ser (Ser160) or the Asn mutant (160Asn) form of<jats:italic>pfap2-mu</jats:italic>. Transgenic parasites carrying the<jats:italic>pfap2-mu</jats:italic>160Asn allele were significantly less sensitive to dihydroartemisinin using a standard 48-h<jats:italic>in vitro</jats:italic>test, providing direct evidence of an altered parasite response to artemisinin. Our data also provide evidence that<jats:italic>pfap2-mu</jats:italic>variants can modulate parasite sensitivity to quinine. No evidence was found that<jats:italic>pfap2-mu</jats:italic>variants contribute to the slow-clearance phenotype exhibited by<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content>in Cambodian patients treated with artesunate monotherapy. These findings provide compelling evidence that<jats:italic>pfap2-mu</jats:italic>can modulate<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content>responses to multiple drugs. We propose that this gene should be evaluated further as a potential molecular marker of antimalarial resistance.</jats:p>

Original publication

DOI

10.1128/aac.04067-14

Type

Journal

Antimicrobial Agents and Chemotherapy

Publisher

American Society for Microbiology

Publication Date

05/2015

Volume

59

Pages

2540 - 2547