Abstract
Chloroquine resistance (PvCQR) in Plasmodium vivax, the most predominant malaria species outside of Africa, is emerging globally. The mechanism and markers of PvCQR remain unknown, hampering molecular surveillance and accurate diagnosis of PvCQR. Now is the time to address PvCQR as technological advances are finally available to overcome the challenges of P. vivax research. Our hypothesis, based on our results from a clinical efficacy study in Vietnam and recently published data from P. vivax parasites adapted to a non-human primate model, is that altered gene expression of transporter genes plays a major role in PvCQR. This research aims to use transcriptomic and transgenic approaches to identify molecular markers and define the mechanism of PvCQR. By capitalizing on a large collection of P. vivax clinical samples (including CQR) and utilizing cutting-edge RNA sequencing technologies (bulk- and single-cell RNAseq), it will be possible to unravel the transcriptional network of genes underlying a PvCQR phenotype and better understand the impact of infection complexity on treatment outcome. P. knowlesi transgenic lines, differentially expressing P. vivax genes, will also be generated using CRISPR/Cas9 genome editing in order to determine drug resistance mechanisms. Outcomes of this research will directly benefit drug efficacy studies, drug resistance surveillance, and create a model suitable for industry to screen compounds for activity against PvCQR.
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