Fitness of artemisinin-resistant Plasmodium falciparum in vitro
Fitness of artemisinin-resistant Plasmodium falciparum in vitro
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DOI：
10.1093/jac/dkv199
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发表时间：
2015-10-01
影响因子：
5.2
通讯作者：
Kyle, Dennis E.
中科院分区：
文献类型：
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作者：
Hott, Amanda;Tucker, Matthew S.;Kyle, Dennis E.
目的：耐药性赋予经常暴露于药物压力下的寄生虫适应性优势，但这些突变也可能会产生适应性成本。我们在体外评估了恶性疟原虫青蒿素耐药性的优势和成本，以了解耐药性在竞争环境中如何传播和演变。方法：采用 SNP 基因分型、药物敏感性分析和拷贝数测定来评估青蒿素耐药性对疟原虫适应性的影响。从同基因亲本克隆（D6）中体外选择的青蒿素抗性克隆（C9）用于进行竞争性生长研究，以评估青蒿素抗性的适应性。将耐药克隆和敏感克隆在存在和不存在药物压力（二氢青蒿素或乙胺嘧啶）的情况下混合或单独生长，以量化青蒿素耐药性获得或丧失的速率。结果：我们通过实验首次证明，青蒿素耐药性提供了一种适应性优势，这种优势在不经常接触药物的情况下会被选择，但在不接触青蒿素药物的情况下就会消失。与青蒿素耐药性的最佳相关性是体外对青蒿素衍生物的药物敏感性降低、Pf3D7_1030100 拷贝数增加以及 Pf3D7_0307600 中的 SNP。 kelch 基因 (Pf3D7_1343700) 中的 E208K 突变 SNP 与耐药性无关。此外，我们观察到乙胺嘧啶诱导的第二周期环期休眠，表明休眠是一种适应性特征，为抗疟药物应激下的生存提供了优势。 结论：即使在不经常接触青蒿素药物的情况下，青蒿素抗性恶性疟原虫也具有生存优势并在种群中占主导地位。
Objectives: Drug resistance confers a fitness advantage to parasites exposed to frequent drug pressure, yet these mutations also may incur a fitness cost. We assessed fitness advantages and costs of artemisinin resistance in Plasmodium falciparum in vitro to understand how drug resistance will spread and evolve in a competitive environment.Methods: Genotyping of SNPs, drug susceptibility assays and copy number determination were used to assess the impact of artemisinin resistance on parasite fitness. An artemisinin-resistant clone (C9) selected in vitro from an isogenic parental clone (D6) was used to conduct competitive growth studies to assess fitness of artemisinin resistance. The resistant and susceptible clones were mixed or grown alone in the presence and absence of drug pressure (dihydroartemisinin or pyrimethamine) to quantify the rate at which artemisinin resistance was gained or lost.Results: We experimentally demonstrate for the first time that artemisinin resistance provides a fitness advantage that is selected for with infrequent exposure to drug, but is lost in the absence of exposure to artemisinin drugs. The best correlations with artemisinin resistance were decreased in vitro drug susceptibility to artemisinin derivatives, increased copy number of Pf3D7_1030100 and an SNP in Pf3D7_0307600. An SNP conferring an E208K mutation in the kelch gene (Pf3D7_1343700) was not associated with resistance. Furthermore, we observed second-cycle ring-stage dormancy induced by pyrimethamine, suggesting that dormancy is a fitness trait that provides an advantage for survival from antimalarial drug stress.Conclusions: Artemisinin-resistant P. falciparum have a fitness advantage to survive and predominate in the population even in the face of infrequent exposure to artemisinin drugs.