ARC3: Artemisin Resistance Confirmation, Characterization and Containment
The Artemisinin Resistance Confirmation, Characterization and Containment (ARC3) project, an international collaboration coordinated by the World Health Organization and funded by the Bill and Melinda Gates foundation, conducted clinical trials of artesunate monotherapy for uncomplicated Plasmodium falciparum malaria in Cambodia, Thailand and Bangladesh. As its title implies, ARC3 aimed to confirm clinical resistance to artemisinins in Southeast Asia, define in vitro drug resistance phenotypes, and identify molecular markers of resistance to guide containment efforts.
As part of ARC3, a collaboration was initiated to prepare for studies using whole genome sequencing and other high throughput genotyping technologies to rapidly identify genetic loci associated with artemisinin resistance. This included identifying signatures of selection in the P. falciparum genome, and conducting genome-wide association studies (GWAS) of parasite isolates with varying parasite clearance times. Leukocyte-depleted venous blood was collected in the ARC3 trials and sequenced through MalariaGEN’s Population Genomics of P. falciparum Project. The goals of this aspect of the ARC3 project were to develop and implement methods to identify candidate markers of drug resistance using outputs from Illumina sequencing. In parallel, ARC3 samples were valuable in helping MalariaGEN to improve sample handling and sequencing methods for field samples. Candidate markers found using this approach are being assessed for their ability to predict clinical manifestations of artemisinin resistance. If validated in replication studies that are now underway, candidate markers will be used to develop surveillance tools to map the distribution of resistance and guide containment efforts.
Lead partner
Chris Plowe
cplowe@medicine.umaryland.edu
Howard Hughes Medical Institute
University of Maryland
Publications
Manske M, Miotto O. et al. Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing. Nature.
DOI: 10.1038/nature11174
ePrint version of article
Venkatesan M. et al. Using CF11 cellulose columns to inexpensively and effectively remove human DNA from Plasmodium falciparum-infected whole blood samples. Malar J. 2012 Feb 10;11:41. PMID 22321373
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