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首页> 外文期刊>The American Journal of Tropical Medicine and Hygiene >Multiple Novel Mutations in Plasmodium falciparum Chloroquine Resistance Transporter Gene during Implementation of Artemisinin Combination Therapy in Thailand
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Multiple Novel Mutations in Plasmodium falciparum Chloroquine Resistance Transporter Gene during Implementation of Artemisinin Combination Therapy in Thailand

机译：泰国蒿属素组合治疗中疟原虫氯喹抗转运蛋白疟原虫抗性转运蛋白多种新突变

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Mutations in the chloroquine resistance transporter gene of Plasmodium falciparum (Pfcrt) are associated with drug susceptibility status of chloroquine and other antimalarials that interfere with heme detoxification process including artemisinin. We aim to investigate whether an increase in duration of artemisinin combination therapy (ACT) in Thailand could affect mutations in Pfcrt. The complete coding sequences of Pfcrt and dihydrofolate reductase (Pfdhfr), and size polymorphisms of the merozoite surface proteins-1 and 2 (Pfmsp-1 and Pfmsp-2) of 189 P. falciparum isolates collected during 1991 and 2016 were analyzed. In total, 12 novel amino acid substitutions and 13 novel PfCRT haplotypes were identified. The most prevalent haplotype belonged to the Dd2 sequence and no wild type was found. A significant positive correlation between the frequency of Pfcrt mutants and the year of sample collection was observed during nationwide ACT implementation (r = 0.780; P = 0.038). The number of haplotypes and nucleotide diversity of isolates collected during 3-day ACT (2009-2016) significantly outnumbered those collected before this treatment regimen. Positive Darwinian selection occurred in the transmembrane domains only among isolates collected during 3-day ACT but not among those collected before this period. No remarkable change was observed in the molecular indices for other loci analyzed when similar comparisons were performed. An increase in the duration of artesunate in combination therapy in Thailand could exert selective pressure on the Pfcrt locus, resulting in emergence of novel variants. The impact of these novel haplotypes on antimalarial susceptibilities requires further study.
机译：疟原虫（PFCRT）的氯喹抗转运蛋白中的突变与氯喹和其他抗疟药的药物敏感性状态有关，干扰血红素排毒过程，包括蒿蛋白。我们的目的是探讨泰国的青蒿素组合治疗（ACT）的持续时间是否会影响PFCRT中的突变。分析了1991年和2016年期间收集于1991年和2016年的Merozoite表面蛋白-1和Merozoite表面蛋白-1和2（PFMSP-1和PFMSP-2）的PFCRT和二羟氢醇还原酶（PFDHFR）的完整编码序列和大小多态性。共有12种新型新型氨基酸取代和13个新的PFCRT单倍型。最普遍的单倍型属于DD2序列，未发现野生类型。在全国范围内的行为实施期间观察到PFCRT突变体频率与样品收集年之间的显着正相关（R = 0.780; P = 0.038）。在3天ACT（2009-2016）期间收集的分离株的单倍型和核苷酸多样性的数量显着超过了该治疗方案之前收集的分离物。阳性Darwinian选择在三天行动期间收集的分离物中仅发生在跨膜结构域中，但在此期间收集的分离物中。在进行类似的比较时，在分析的其他基因座的分子指标中没有观察到显着变化。泰国联合治疗中的艺术持续时间持续时间可能对PFCRT基因座的选择性压力施加，导致新型变异的出现。这些新型单型对抗疟疾敏感性的影响需要进一步研究。

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