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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Competitive release and facilitation of drug-resistant parasites after therapeutic chemotherapy in a rodent malaria model
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Competitive release and facilitation of drug-resistant parasites after therapeutic chemotherapy in a rodent malaria model

机译：啮齿动物疟疾模型中治疗性化疗后抗药性寄生虫的竞争释放和促进

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Malaria infections frequently consist of mixtures of drug-resistant and drug-sensitive parasites. If crowding occurs, where clonal population densities are suppressed by the presence of coinfecting clones, removal of susceptible clones by drug treatment could allow resistant clones to expand into the newly vacated niche space within a host. Theoretical models show that, if such competitive release occurs, it can be a potent contributor to the strength of selection, greatly accelerating the rate at which resistance spreads in a population. A variety of correlational field data suggest that competitive release could occur in human malaria populations, but direct evidence cannot be ethically obtained from human infections. Here we show competitive release after py-rimethamine curative chemotherapy of acute infections of the rodent malaria Plasmodium chabaudi in laboratory mice. The expansion of resistant parasite numbers after treatment resulted in enhanced transmission-stage densities. After the elimination or near-elimination of sensitive parasites, the number of resistant parasites increased beyond that achieved when a competitor had never been present. Thus, a substantial competitive release occurred, markedly elevating the fitness advantages of drug resistance above those arising from survival alone. This finding may explain the rapid spread of drug resistance and the subsequently brief useful lifespans of some antimalarial drugs. In a second experiment, where subcurative chemotherapy was administered, the resistant clone was only partly released from competitive suppression and experienced a restriction in the size of its expansion after treatment. This finding raises the prospect of harnessing in-host ecology to slow the spread of drug resistance.
机译：疟疾感染通常由耐药性和药敏性寄生虫的混合物组成。如果发生拥挤，而合并感染的克隆会抑制克隆种群的密度，那么通过药物处理去除易感克隆可能会使抗性克隆扩展到宿主内新腾出的利基空间。理论模型表明，如果发生这种竞争性释放，则可能是选择强度的有力贡献者，从而大大加快了抗性在人群中扩散的速度。各种相关的现场数据表明，竞争性释放可能发生在人类疟疾人群中，但不能从伦理上从人类感染中获得直接证据。在这里，我们显示了在对小鼠进行的啮齿动物疟疾Chabaudi疟原虫的急性感染后，对次甲基苯丙胺的治愈性化疗后的竞争释放。治疗后抗药性寄生虫数量的增加导致传播期密度的增加。在消除或几乎消除了敏感的寄生虫之后，耐药性寄生虫的数量增加，超过了从未出现过竞争对手的数量。因此，发生了实质性的竞争释放，显着提高了耐药性的适应性优势，使其超过了仅由生存引起的优势。这一发现可能解释了耐药性的迅速蔓延以及某些抗疟疾药物的短暂使用寿命。在第二个实验中，在进行亚治愈性化疗的情况下，抗性克隆仅从竞争性抑制中部分释放，并且在治疗后其扩增大小受到限制。这一发现提出了利用宿主生态系统减缓耐药性扩散的前景。

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