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<jats:title>ABSTRACT</jats:title><jats:p>Chloroquine (CQ)-resistant<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Plasmodium vivax</jats:named-content>is present in most countries where<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. vivax</jats:named-content>infection is endemic, but the underlying molecular mechanisms responsible remain unknown. Increased expression of<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. vivax</jats:named-content><jats:italic>crt-o</jats:italic>(<jats:italic>pvcrt-o</jats:italic>) has been correlated with<jats:italic>in vivo</jats:italic>CQ resistance in an area with low-grade resistance. We assessed<jats:italic>pvcrt-o</jats:italic>expression in isolates from Papua (Indonesia), where<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. vivax</jats:named-content>is highly CQ resistant.<jats:italic>Ex vivo</jats:italic>drug susceptibilities to CQ, amodiaquine, piperaquine, mefloquine, and artesunate were determined using a modified schizont maturation assay. Expression levels of<jats:italic>pvcrt-o</jats:italic>were measured using a novel real-time quantitative reverse transcription-PCR method. Large variations in<jats:italic>pvcrt-o</jats:italic>expression were observed across the 51 isolates evaluated, with the fold change in expression level ranging from 0.01 to 59 relative to that seen with the<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. vivax</jats:named-content>β-tubulin gene and from 0.01 to 24 relative to that seen with the<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. vivax</jats:named-content>aldolase gene. Expression was significantly higher in isolates with the majority of parasites at the ring stage of development (median fold change, 1.7) compared to those at the trophozoite stage (median fold change, 0.5;<jats:italic>P</jats:italic>&lt; 0.001). Twenty-nine isolates fulfilled the criteria for<jats:italic>ex vivo</jats:italic>drug susceptibility testing and showed high variability in CQ responses (median, 107.9 [range, 6.5 to 345.7] nM). After controlling for the parasite stage, we found that<jats:italic>pvcrt-o</jats:italic>expression levels did not correlate with the<jats:italic>ex vivo</jats:italic>response to CQ or with that to any of the other antimalarials tested. Our results highlight the importance of development-stage composition for measuring<jats:italic>pvcrt-o</jats:italic>expression and suggest that<jats:italic>pvcrt-o</jats:italic>transcription is not a primary determinant of<jats:italic>ex vivo</jats:italic>drug susceptibility. A comprehensive transcriptomic approach is warranted for an in-depth investigation of the role of gene expression levels and<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. vivax</jats:named-content>drug resistance.</jats:p>

Original publication

DOI

10.1128/aac.02207-15

Type

Journal

Antimicrobial Agents and Chemotherapy

Publisher

American Society for Microbiology

Publication Date

01/2016

Volume

60

Pages

361 - 367