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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Spontaneous mutations in the Plasmodium falciparum sarcoplasmic/ endoplasmic reticulum Ca2+-ATPase (PfATP6) gene among geographically widespread parasite populations unexposed to artemisinin-based combination therapies.
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Spontaneous mutations in the Plasmodium falciparum sarcoplasmic/ endoplasmic reticulum Ca2+-ATPase (PfATP6) gene among geographically widespread parasite populations unexposed to artemisinin-based combination therapies.

机译：未暴露于基于青蒿素的联合治疗中的地域广泛的寄生虫人群中的恶性疟原虫浆质/内质网Ca2 + -ATPase（PfATP6）基因的自发突变。

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摘要

Recent reports on the decline of the efficacy of artemisinin-based combination therapies (ACTs) indicate a serious threat to malaria control. The endoplasmic/sarcoplasmic reticulum Ca(2+)-ATPase ortholog of Plasmodium falciparum (PfSERCA) has been suggested to be the target of artemisinin and its derivatives. It is assumed that continuous artemisinin pressure will affect polymorphism of the PfSERCA gene (serca) if the protein is the target. Here, we investigated the polymorphism of serca in parasite populations unexposed to ACTs to obtain baseline information for the study of potential artemisinin-driven selection of resistant parasites. Analysis of 656 full-length sequences from 13 parasite populations in Africa, Asia, Oceania, and South America revealed 64 single nucleotide polymorphisms (SNPs), of which 43 were newly identified and 38 resulted in amino acid substitutions. No isolates showed L263E and S769N substitutions, which were reportedly associated with artemisinin resistance. Among the four continents, the number of SNPs was highest in Africa. In Africa, Asia, and Oceania, common SNPs, or those with a minor allele frequency of >/=0.05, were less prevalent, with most SNPs noted to be continent specific, whereas in South America, common SNPs were highly prevalent and often shared with those in Africa. Of 50 amino acid haplotypes observed, only one haplotype (3D7 sequence) was seen in all four continents (64%). Forty-eight haplotypes had frequencies of less than 5%, and 40 haplotypes were continent specific. The geographical difference in the diversity and distribution of serca SNPs and haplotypes lays the groundwork for assessing whether some artemisinin resistance-associated mutations and haplotypes are selected by ACTs.
机译：最近有关基于青蒿素的联合疗法（ACT）疗效下降的报道表明，疟疾控制受到严重威胁。恶性疟原虫（PfSERCA）的内质网/肌质网Ca（2 +）-ATPase直系同源物已被认为是青蒿素及其衍生物的靶标。假设如果蛋白是靶标，持续的青蒿素压力将影响PfSERCA基因（serca）的多态性。在这里，我们调查未暴露于ACTs的寄生虫种群中浆膜的多态性，以获得基线信息，以研究潜在的青蒿素驱动的抗性寄生虫选择。对来自非洲，亚洲，大洋洲和南美的13个寄生虫种群的656个全长序列的分析揭示了64个单核苷酸多态性（SNP），其中新鉴定出43个单核苷酸多态性，其中38个导致氨基酸置换。没有分离株显示出L263E和S769N取代，据报道它们与青蒿素耐药有关。在四大洲中，SNP的数量在非洲最高。在非洲，亚洲和大洋洲，常见的SNP或等位基因次要频率> / = 0.05的SNP较少，大多数SNP被指出是特定于大陆的，而在南美，常见的SNP高度流行并且经常共享与非洲的人在一起。在观察到的50个氨基酸单倍型中，在所有四大洲中仅观察到一个单倍型（3D7序列）（64％）。 48个单倍型的频率小于5％，而40个单倍型是特定于大陆的。浆膜SNP和单倍型的多样性和分布的地理差异为评估ACT是否选择了一些与青蒿素抗性相关的突变和单倍型奠定了基础。

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