Data from: Understanding genetic variation in in vivo tolerance to artesunate: implications for treatment efficacy and resistance monitoring

Artemisinin-based drugs are the front-line weapon in the treatment of human malaria cases, but there is concern that recent reports of slow clearing infections may signal developing resistance to treatment. In the absence of molecular markers for resistance, current efforts to monitor drug efficacy are based on the rate at which parasites are cleared from infections. However, some knowledge of the standing variation in parasite susceptibility is needed to identify a meaningful increase in infection half-life. Here, we show that five previously unexposed genotypes of the rodent malaria parasite Plasmodium chabaudi differ substantially in their in vivo response to treatment. Slower clearance rates were not linked to parasite virulence or growth rate, going against the suggestion that drug treatment will drive the evolution of virulence in this system. The level of variation observed here in a relatively small number of genotypes suggests existing ‘resistant’ parasites could be present in the population and therefore, increased parasite clearance rates could represent selection on pre-existing variation rather than de novo resistance events. This has implications for resistance monitoring as susceptibility may depend on evolved traits unrelated to drug exposure.

青蒿素类药物（Artemisinin-based drugs）是治疗人类疟疾的一线用药，但近期有报告称感染清除速度放缓，这可能预示着治疗相关耐药性的产生，对此学界已引发担忧。由于目前尚未发现耐药性的分子标志物，当前监测药物疗效的工作均以感染个体体内寄生虫的清除速率为依据。然而，若要精准识别感染半衰期具有统计学意义的升高，需先掌握寄生虫药物易感性的现存遗传变异（standing variation）相关信息。本研究表明，5株未接触过抗疟药物的查氏疟原虫（Plasmodium chabaudi）的基因型，在体内治疗应答方面存在显著差异。更慢的寄生虫清除速率与寄生虫毒力或生长速率并无关联，这与“该系统中药物治疗会推动毒力演化”的假说相悖。本研究在少量基因型中观测到的变异程度表明，群体中可能已存在“耐药”寄生虫；由此可见，寄生虫清除速率的提升，可能是对群体中预先存在的遗传变异（pre-existing variation）的选择结果，而非新发耐药事件所致。这一发现对耐药性监测工作具有重要启示：寄生虫的药物易感性可能取决于与药物暴露无关的演化性状。