Infection Analytics Program, Kirby Institute, UNSW Sydney, Kensington, NSW 2052, Australia.
Malaria Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD 4006, Australia.
Int J Parasitol. 2018 Oct;48(12):903-913. doi: 10.1016/j.ijpara.2018.05.010. Epub 2018 Sep 1.
A major mechanism of host-mediated control of blood-stage Plasmodium infection is thought to be removal of parasitized red blood cells (pRBCs) from circulation by the spleen or phagocytic system. The rate of parasite removal is thought to be further increased by anti-malarial drug treatment, contributing to the effectiveness of drug therapy. It is difficult to directly compare pRBC removal rates in the presence and absence of treatment, since in the absence of treatment the removal rate of parasites is obscured by the extent of ongoing parasite proliferation. Here, we transfused a single generation of fluorescently-labelled Plasmodium berghei pRBCs into mice, and monitored both their disappearance from circulation, and their replication to produce the next generation of pRBCs. In conjunction with a new mathematical model, we directly estimated host removal of pRBCs during ongoing infection, and after drug treatment. In untreated mice, pRBCs were removed from circulation with a half-life of 15.1 h. Treatment with various doses of mefloquine/artesunate did not alter the pRBC removal rate, despite blocking parasite replication effectively. An exception was high dose artesunate, which doubled the rate of pRBC removal (half-life of 9.1 h). Phagocyte depletion using clodronate liposomes approximately halved the pRBC removal rate during untreated infection, indicating a role for phagocytes in clearance. We next assessed the importance of pRBC clearance for the decrease in the parasite multiplication rate after high dose artesunate treatment. High dose artesunate decreased parasite replication ∼46-fold compared with saline controls, with inhibition of replication contributing 23-fold of this, and increased pRBC clearance contributing only a further 2.0-fold. Thus, in our in vivo systems, drugs acted primarily by inhibiting parasite replication, with drug-induced increases in pRBC clearance making only minor contributions to overall drug effect.
机体介导的控制血期疟原虫感染的主要机制被认为是脾脏或吞噬系统将寄生的红细胞（pRBC）从循环中清除。抗疟药物治疗被认为进一步增加了寄生虫的清除率，这有助于药物治疗的效果。由于在没有治疗的情况下，寄生虫的清除率被持续的寄生虫增殖程度所掩盖，因此很难直接比较治疗前后的 pRBC 清除率。在这里，我们将一代荧光标记的恶性疟原虫 pRBC 输注到小鼠体内，并监测它们从循环中消失以及它们复制产生下一代 pRBC 的情况。结合一个新的数学模型，我们直接估计了宿主在持续感染和药物治疗后对 pRBC 的清除率。在未治疗的小鼠中，pRBC 从循环中清除的半衰期为 15.1 小时。用不同剂量的甲氟喹/青蒿琥酯治疗并没有改变 pRBC 的清除率，尽管有效地阻止了寄生虫的复制。青蒿琥酯高剂量治疗是一个例外，它使 pRBC 的清除率增加了一倍（半衰期为 9.1 小时）。用氯膦酸脂质体耗尽吞噬细胞会使未治疗感染时的 pRBC 清除率减半，表明吞噬细胞在清除中起作用。我们接下来评估了在高剂量青蒿琥酯治疗后，pRBC 清除率对寄生虫倍增率降低的重要性。高剂量青蒿琥酯使寄生虫复制减少了约 46 倍，与生理盐水对照相比，抑制复制的贡献了 23 倍，而增加的 pRBC 清除率仅贡献了进一步的 2.0 倍。因此，在我们的体内系统中，药物主要通过抑制寄生虫复制起作用，药物诱导的 pRBC 清除率增加对整体药物效果的贡献很小。
