Local emergence in Amazonia of Plasmodium falciparum k13 C580Y mutants associated with in vitro artemisinin resistance
Local emergence in Amazonia of Plasmodium falciparum k13 C580Y mutants associated with in vitro artemisinin resistance
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DOI：
10.7554/elife.51015
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发表时间：
2020-05-12
期刊：
影响因子：
7.7
通讯作者：
Musset, Lise
中科院分区：
文献类型：
--
作者：
Mathieu, Luana C.;Cox, Horace;Musset, Lise
抗疟药物耐药性在历史上是通过东南亚和南美洲恶性疟原虫寄生虫群体中的会聚性新生突变而产生的。在过去的十年中，在东南亚，青蒿素作为一线抗疟疗法的核心成分，经历了与几种pfk 13突变（主要是C580 Y）相关的寄生虫清除延迟。我们报告说，突变pfk 13已独立出现在圭亚那，基因组分析表明，从东南亚不同的进化起源。2016-2017年在圭亚那收集的样本中，有1.6%（14/854）发现了Pfk 13 C580 Y寄生虫。通过基因编辑将pfk 13 C580 Y或R539 T突变引入当地寄生虫，可获得高水平的体外青蒿素耐药性。体外生长竞争试验揭示了与这些pfk 13变异体相关的适应性成本，这可能解释了为什么这些抗性等位基因在南美洲的频率没有更快地增加。这些数据使当地的疟疾控制工作处于危险之中。所有推荐的疟疾治疗方法都包括一种叫做青蒿素或其衍生物的药物。然而，人们担心引起大多数疟疾病例的恶性疟原虫最终会对这种药物产生广泛的抗药性。2008年，在柬埔寨发现了一种对青蒿素具有部分抗药性的恶性疟原虫，此后它在东南亚蔓延。这种耐药性似乎经常与一种称为pfk 13 C580 Y的突变有关。东南亚和亚马逊地区被认为是抗疟药物耐药性的热点地区，2010年在南美洲国家圭亚那检测到了pfk 13 C580 Y突变。为了检查这种突变是否仍在世界这一地区传播，Mathieu等人在2016年至2017年期间收集并分析了圭亚那的854个样本。总体而言，1.6%的样本具有pfk 13 C580 Y突变，但在一个区域中该数字高达8.8%。进一步的分析表明，圭亚那的突变并没有从东南亚传播，而是在亚马逊河流域独立发生。为了更好地了解pfk 13 C580 Y突变的影响，Mathieu等人将这种遗传变化引入了来自圭亚那邻国的非耐药寄生虫。正如预期的那样，这种突变使恶性疟原虫对青蒿素具有高度抗药性，但也减缓了寄生虫的生长速度。这一不利因素可以解释为什么近年来这种突变没有在圭亚那迅速传播，青蒿素及其衍生物总是与其他抗疟药物联合使用，以减缓抗药性的发展;人们担心，对青蒿素敏感性的降低会导致寄生虫对伙伴药物产生抗药性。需要进一步的研究来评估pfk 13 C580 Y突变如何影响寄生虫对给予患者的典型药物组合的反应。
Antimalarial drug resistance has historically arisen through convergent de novo mutations in Plasmodium falciparum parasite populations in Southeast Asia and South America. For the past decade in Southeast Asia, artemisinins, the core component of first-line antimalarial therapies, have experienced delayed parasite clearance associated with several pfk13 mutations, primarily C580Y. We report that mutant pfk13 has emerged independently in Guyana, with genome analysis indicating an evolutionary origin distinct from Southeast Asia. Pfk13 C580Y parasites were observed in 1.6% (14/854) of samples collected in Guyana in 2016-2017. Introducing pfk13 C580Y or R539T mutations by gene editing into local parasites conferred high levels of in vitro artemisinin resistance. In vitro growth competition assays revealed a fitness cost associated with these pfk13 variants, potentially explaining why these resistance alleles have not increased in frequency more quickly in South America. These data place local malaria control efforts at risk in the Guiana Shield.eLife digest All recommended treatments against malaria include a drug called artemisinin or some of its derivatives. However, there are concerns that Plasmodium falciparum, the parasite that causes most cases of malaria, will eventually develop widespread resistance to the drug. A strain of P. falciparum partially resistant to artemisinin was seen in Cambodia in 2008, and it has since spread across Southeast Asia. The resistance appears to be frequently linked to a mutation known as pfk13 C580Y.Southeast Asia and Amazonia are considered to be hotspots for antimalarial drug resistance, and the pfk13 C580Y mutation was detected in the South American country of Guyana in 2010. To examine whether the mutation was still circulating in this part of the world, Mathieu et al. collected and analyzed 854 samples across Guyana between 2016 and 2017. Overall, 1.6% of the samples had the pfk13 C580Y mutation, but this number was as high as 8.8% in one region. Further analyses revealed that the mutation in Guyana had not spread from Southeast Asia, but that it had occurred in Amazonia independently.To better understand the impact of the pfk13 C580Y mutation, Mathieu et al. introduced this genetic change into non-resistant parasites from a country neighbouring Guyana. As expected, the mutation made P. falciparum highly resistant to artemisinin, but it also slowed the growth rate of the parasite. This disadvantage may explain why the mutation has not spread more rapidly through Guyana in recent years.Artemisinin and its derivatives are always associated with other antimalarial drugs to slow the development of resistance; there are concerns that reduced susceptibility to artemisinin leads to the parasites becoming resistant to the partner drugs. Further research is needed to evaluate how the pfk13 C580Y mutation affects the parasite's response to the typical combination of drugs that are given to patients.