Centro de Malaria & Doenças Tropicais, LA/IHMT/Universidade Nova de Lisboa, Lisbon, Portugal.
Infect Genet Evol. 2013 Mar;14:340-6. doi: 10.1016/j.meegid.2012.12.011. Epub 2013 Jan 11.
If drug-resistant malaria mutants are less fit than sensitive forms, they will wane over time when active drug pressure is removed and the overall sensitivity to the drug may be restored. However, most studies addressing this issue have been largely retrospective. Here, we undertook a predictive study, using mutant rodent malaria parasites resistant to the Artemisinin combination treatment (ACT) version of artesunate+mefloquine (ATN+MF) to gain insights about their ability to compete with ATN+MF-sensitive forms in untreated hosts. Previously, Plasmodium chabaudi parasites resistant to ATN+MF were selected in vivo through prolonged passaging in mice under increasing doses of the two drugs, and shown to harbour duplication of the mdr1 gene. Here, the resistant parasite, AS-ATNMF1, was mixed with its progenitor AS-ATN in different proportions and each mixture was injected into mice that were left untreated. Absolute percentage parasitaemias and the proportion of each parasite were then monitored by microscopy and proportional sequencing, respectively, every two days for a period of 14days. AS-ATNMF1 outperformed its progenitor AS-ATN over the whole sampling period regardless of the relative starting proportion of each parasite clone. In order to assess if consecutive sub-inoculations could have been responsible for the apparent fitness gain of the resistant parasite, its growth was compared to that of AS-ATN27P, a parasite which was passaged the same number of times as AS-ATNMF1, but left untreated. Although small fluctuations in the proportion of each parasite were observed through time, the relative abundance of each on the last day of sampling (Day 14) was virtually identical to that of the starting inoculum. We conclude that there is no fitness cost associated with MDR1-associated ATN+MF resistance in vivo. These observations offer the first insights about the within-host dynamics between ACT-resistant and -sensitive parasites in absence of drug pressure.
如果抗药性疟原虫突变体的适应性不如敏感形式，那么在活性药物压力消除后，随着时间的推移，它们会逐渐减少，而药物的总体敏感性可能会恢复。然而，大多数解决这个问题的研究主要是回顾性的。在这里，我们进行了一项预测性研究，使用对青蒿素联合治疗（ACT）版青蒿琥酯+甲氟喹（ATN+MF）具有抗药性的突变啮齿类疟原虫，以深入了解它们在未经治疗的宿主中与 ATN+MF 敏感形式竞争的能力。此前，通过在小鼠体内长时间传代，在两种药物剂量不断增加的情况下，对 Plasmodium chabaudi 寄生虫进行了抗 ATN+MF 的选择，并显示出 mdr1 基因的重复。在这里，将具有抗药性的寄生虫 AS-ATNMF1 与它的亲本 AS-ATN 以不同的比例混合，并将每种混合物注入未接受治疗的小鼠体内。然后，通过显微镜分别监测绝对寄生虫血症百分比和每种寄生虫的比例，每天监测两次，持续 14 天。无论每个寄生虫克隆的起始相对比例如何，AS-ATNMF1 在整个采样期间都优于其亲本 AS-ATN。为了评估连续的亚接种是否可能导致抗药性寄生虫的明显适应性增加，将其生长与 AS-ATN27P 进行了比较，AS-ATN27P 与 AS-ATNMF1 传代次数相同，但未接受治疗。尽管随着时间的推移，每种寄生虫的比例略有波动，但在采样的最后一天（第 14 天），每种寄生虫的相对丰度与起始接种物几乎相同。我们得出结论，在体内不存在药物压力的情况下，与 MDR1 相关的 ATN+MF 抗药性没有适应性成本。这些观察结果提供了在没有药物压力的情况下，ACT 耐药和敏感寄生虫之间的宿主内动态的第一个见解。
