Data from: Chemotherapy, within-host ecology and the fitness of drug-resistant malaria parasites

A major determinant of the rate at which drug-resistant malaria parasites spread through a population is the ecology of resistant and sensitive parasites sharing the same host. Drug treatment can significantly alter this ecology by removing the drug-sensitive parasites, leading to competitive release of resistant parasites. Here, we test the hypothesis that the spread of resistance can be slowed by reducing drug treatment and hence restricting competitive release. Using the rodent malaria model Plasmodium chabaudi, we found that low-dose chemotherapy did reduce competitive release. A higher drug dose regimen exerted stronger positive selection on resistant parasites for no detectable clinical gain. We estimated instantaneous selection coefficients throughout the course of replicate infections to analyze the temporal pattern of the strength and direction of within-host selection. The strength of selection on resistance varied through the course of infections, even in untreated infections, but increased immediately following drug treatment, particularly in the high-dose groups. Resistance remained under positive selection for much longer than expected from the half life of the drug. Although there are many differences between mice and people, our data do raise the question whether the aggressive treatment regimens aimed at complete parasite clearance are the best resistance-management strategies for humans.

抗药性疟原虫在种群中传播速率的主要决定因素之一，是共享同一宿主的抗药性与敏感性疟原虫的宿主内生态。药物治疗可通过清除药物敏感性疟原虫，显著改变这一生态，进而引发抗药性疟原虫的竞争释放。本研究检验了如下假说：减少药物治疗、从而限制竞争释放，可延缓抗药性的传播。我们以啮齿类疟原虫模型查氏疟原虫（Plasmodium chabaudi）开展实验，结果显示低剂量化疗确实能够降低竞争释放程度。更高剂量的给药方案会对抗药性疟原虫产生更强的正向选择，却未带来可检测到的临床获益。我们通过对重复感染全过程的瞬时选择系数进行估算，分析了宿主内选择作用的强度与方向随时间变化的模式。结果发现，即便在未接受药物治疗的感染组中，抗药性相关选择的强度也会随感染进程发生变化；而在药物治疗后，选择强度会立即升高，这一现象在高剂量给药组中尤为显著。抗药性相关的正向选择持续时长远超基于药物半衰期的预期值。尽管小鼠与人类的生理存在诸多差异，但本研究数据仍提出了一个值得探讨的问题：旨在完全清除寄生虫的激进治疗方案，是否是人类抗药性管理的最优策略？