Tracking Origins and Spread of Sulfadoxine-Resistant Plasmodium falciparum dhps Alleles in Thailand

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Abstract
The emergence and spread of drug-resistant Plasmodium falciparum have been a major impediment for the control of malaria worldwide. Earlier studies have shown that similar to chloroquine (CQ) resistance, high levels of pyrimethamine resistance in P. falciparum originated independently 4 to 5 times globally, including one origin at the Thailand-Cambodia border. In this study we describe the origins and spread of sulfadoxine-resistance-conferring dihydropteroate synthase ( dhps ) alleles in Thailand. The dhps mutations and flanking microsatellite loci were genotyped for P. falciparum isolates collected from 11 Thai provinces along the Burma, Cambodia, and Malaysia borders. Results indicated that resistant dhps alleles were fixed in Thailand, predominantly being the S GEG A, AGE AA, and S GNG A triple mutants and the AG KAA double mutant (mutated codons are underlined). These alleles had different geographical distributions. The S GEG A alleles were found mostly at the Burma border, while the S GNG A alleles occurred mainly at the Cambodia border and nearby provinces. Microsatellite data suggested that there were two major genetic lineages of the triple mutants in Thailand, one common for S GEG A/S GNG A alleles and another one independent for AGE AA. Importantly, the newly reported S GNG A alleles possibly originated at the Thailand-Cambodia border. All parasites in the Yala province (Malaysia border) had AG KAA alleles with almost identical flanking microsatellites haplotypes. They were also identical at putatively neutral loci on chromosomes 2 and 3, suggesting a clonal nature of the parasite population in Yala. In summary, this study suggests multiple and independent origins of resistant dhps alleles in Thailand.