Malaria parasites can develop stable resistance to artemisinin but lack mutations in candidate genes atp6 (Encoding the sarcoplasmic and endoplasmic reticulum Ca2+ ATPase), tctp, mdr1, and cg10
Malaria parasites can develop stable resistance to artemisinin but lack mutations in candidate genes atp6 (Encoding the sarcoplasmic and endoplasmic reticulum Ca2+ ATPase), tctp, mdr1, and cg10
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DOI：
10.1128/aac.50.2.480-489.2006
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发表时间：
2006-02-01
影响因子：
4.9
通讯作者：
Cravo, P
中科院分区：
文献类型：
--
作者：
Afonso, A;Hunt, P;Cravo, P
恶性疟原虫对氯喹和磺胺多辛-乙胺嘧啶等药物的耐药性是疟疾控制中的一个主要问题。因此，青蒿素（ART）衍生物，特别是与其他药物联合使用，越来越多地用于治疗疟疾，降低了出现对这些成分具有耐药性的寄生虫的可能性。虽然尚未从实验室或实地研究中报告对青蒿素的稳定耐药性，但由于缺乏替代治疗，它的出现将是灾难性的。在这里，据我们所知，我们首次报告了遗传稳定且可传播的抗ART和抗青蒿琥酯（ATN）疟疾寄生虫。在ART或ATN浓度增加的情况下生长的两种啮齿动物疟原虫chabaudi chabaudi Plosmodium chabaudi对ART和ATN的抗性分别增加了15倍和6倍。经过克隆、冻融、无药传代和蚊虫传播，抗性保持稳定。比较了敏感和耐药疟原虫可能的抗逆转录病毒耐药性基因调控因子mdr1、cg10、tctp和atp6的核苷酸序列。这些基因未发现突变。此外，我们调查了这些基因拷贝数的变化是否可以解释抗性，但发现抗性寄生虫保留了与其敏感祖先相同的拷贝数。我们认为，这是首次报道对青蒿素或其衍生物具有遗传稳定和可传播耐药性的疟疾寄生虫。
Resistance of Plasmodium falciparum to drugs such as chloroquine and sulfadoxine-pyrimethamine is a major problem in malaria control. Artemisinin (ART) derivatives, particularly in combination with other drugs, are thus increasingly used to treat malaria, reducing the probability that parasites resistant to the components will emerge. Although stable resistance to artemisinin has yet to be reported from laboratory or field studies, its emergence would be disastrous because of the lack of alternative treatments. Here, we report for the first time, to our knowledge, genetically stable and transmissible ART and artesunate (ATN)-resistant malaria parasites. Each of two lines of the rodent malaria parasite Plosmodium chabaudi chabaudi, grown in the presence of increasing concentrations of ART or ATN, showed 15-fold and 6-fold increased resistance to ART and ATN, respectively. Resistance remained stable after cloning, freeze-thawing, after passage in the absence of drug, and transmission through mosquitoes. The nucleotide sequences of the possible genetic modulators of ART resistance (mdr1, cg10, tctp, and atp6) of sensitive and resistant parasites were compared. No mutations in these genes were identified. In addition we investigated whether changes in the copy number of these genes could account for resistance but found that resistant parasites retained the same number of copies as their sensitive progenitors. We believe that this is the first report of a malaria parasite with genetically stable and transmissible resistance to artemisinin or its derivatives.