Altered temporal response of malaria parasites determines differential sensitivity to artemisinin
Altered temporal response of malaria parasites determines differential sensitivity to artemisinin
复制标题
DOI：
10.1073/pnas.1217452110
复制
发表时间：
2013-03-26
影响因子：
11.1
通讯作者：
Tilley, Leann
中科院分区：
文献类型：
--
作者：
Klonis, Nectarios;Xie, Stanley C.;Tilley, Leann
关于一线青蒿素抗疟药物出现耐药性的报告表明，确定耐药性机制和确定体外耐药性相关因素至关重要。在这里，我们结合联合收割机独特的体外实验和分析方法，以模拟体内药物暴露，努力提供深入了解耐药机制。紧密同步的寄生虫暴露于短的药物脉冲表现出大的阶段依赖性差异，在他们的药物反应，与血红蛋白消化在整个无性周期的大部分。因此，尽管我们鉴定了一个表现出超敏反应的环亚群（侵入后2-4小时），但环期寄生虫对短药物脉冲的敏感性比滋养体低100倍以上。我们发现，在标准体外测定中显示药物敏感性差异很小的实验室菌株在暴露于短药物脉冲时显示出显著（>95倍）的敏感性差异。这些阶段和菌株依赖性的药物敏感性差异反映了不同的反应滞后时间，环显示滞后时间长达4小时。一个简单的模型，假设寄生虫的经验，饱和的有效药物剂量描述了寄生虫的生存能力对药物浓度和暴露时间的复杂依赖性，并被用来证明寄生虫的药物反应曲线的微小变化可以显着改变青蒿素的敏感性。这项工作表明，有效的电阻可以产生fromthe药物的体内半衰期短和特定阶段的滞后时间之间的相互作用，并提供了框架，了解药物作用和寄生虫的耐药性的机制。
Reports of emerging resistance to first-line artemisinin antimalarials make it critical to define resistance mechanisms and identify in vitro correlates of resistance. Here we combine unique in vitro experimental and analytical approaches to mimic in vivo drug exposure in an effort to provide insight into mechanisms of drug resistance. Tightly synchronized parasites exposed to short drug pulses exhibit large stage-dependent differences in their drug response that correlate with hemoglobin digestion throughout most of the asexual cycle. As a result, ring-stage parasites can exhibit >100-fold lower sensitivity to short drug pulses than trophozoites, although we identify a subpopulation of rings (2-4 h postinvasion) that exhibits hypersensitivity. We find that laboratory strains that show little differences in drug sensitivity in standard in vitro assays exhibit substantial (>95-fold) difference in sensitivity when exposed to short drug pulses. These stage-and strain-dependent differences in drug sensitivity reflect differential response lag times with rings exhibiting lag times of up to 4 h. A simple model that assumes that the parasite experiences a saturable effective drug dose describes the complex dependence of parasite viability on both drug concentration and exposure time and is used to demonstrate that small changes in the parasite's drug response profile can dramatically alter the sensitivity to artemisinins. This work demonstrates that effective resistance can arise fromthe interplay between the short in vivo half-life of the drug and the stage-specific lag time and provides the framework for understanding the mechanisms of drug action and parasite resistance.