Rapid response to selection, competitive release and increased transmission potential of artesunate-selected Plasmodium chabaudi malaria parasites.
Rapid response to selection, competitive release and increased transmission potential of artesunate-selected Plasmodium chabaudi malaria parasites.
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DOI：
10.1371/journal.ppat.1004019
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发表时间：
2014-04
期刊：
影响因子：
6.7
通讯作者：
Read AF
中科院分区：
文献类型：
--
作者：
Pollitt LC;Huijben S;Sim DG;Salathé RM;Jones MJ;Read AF
耐药性的演变是我们治疗和控制感染能力的一个关键挑战，它取决于两个过程：重新产生耐药性突变，以及耐药性突变体在人群中的选择和传播。了解影响这两个过程速率的因素对于最大限度地延长药物的有效寿命，从而有效地控制疾病至关重要。对于疟疾寄生虫来说，以青蒿素为基础的药物是抗击疾病的一线武器，但来自该领域的报告显示，在药物治疗期间寄生虫清除率较慢，这令人担心这些药物的有效寿命可能有限。较慢的清除率是否代表真正的耐药性，以及这如何为寄生虫提供选择优势尚不确定。在这里，我们表明，通过逐步增加药物剂量而选择对青蒿琥酯（一种青蒿素衍生物）产生耐药性的chabaudi疟原虫非常迅速地进化出较慢的清除率。在单次感染中，这些较慢的清除率（与现场观察到的相似）通过增加总体密度、治疗后复发和增加传播潜力，为寄生虫提供了适应性优势。在混合感染中，通过药物治疗清除易感寄生虫导致耐药寄生虫的密度和传播潜力大幅增加（竞争性释放）。我们的研究结果证明了耐药性管理的双刃剑：在我们最初的选择实验中，没有寄生虫在积极的化疗中存活，但在选择之后，抗性寄生虫的适应度优势在高剂量药物下最大。对混合感染的积极治疗导致耐药寄生虫在配子体池中占主导地位，而没有为宿主提供额外的健康益处。较慢的清除率可以迅速演变，并且可以在单一和混合菌株感染的药物治疗期间提供强大的适应度优势。耐药性的演变是21世纪医学面临的重大挑战。就疟疾寄生虫而言，这一点尤其明显，因为每种药物的引入都伴随着耐药寄生虫的迅速发展和传播。没有持续不断的新药供应来替代那些不再有效的药物，了解导致耐药性在寄生虫种群中选择和传播的过程是很重要的，这样才能最大限度地延长现有药物的有效寿命。在这里，我们使用一个啮齿动物疟疾模型系统来尝试选择对当前一线疟疾药物青蒿素的敏感性降低的动物。然后，我们研究了耐药寄生虫在单次感染中的生长和传播潜力，以及在药物治疗宿主中与易感寄生虫（混合感染）的竞争。我们表明，选择对药物敏感性较低的寄生虫在两种情况下都具有更高的适应性。我们的研究结果还表明，在选择治疗方案时，应评估和考虑不同治疗方案对耐药性传播速度的影响。
The evolution of drug resistance, a key challenge for our ability to treat and control infections, depends on two processes: de-novo resistance mutations, and the selection for and spread of resistant mutants within a population. Understanding the factors influencing the rates of these two processes is essential for maximizing the useful lifespan of drugs and, therefore, effective disease control. For malaria parasites, artemisinin-based drugs are the frontline weapons in the fight against disease, but reports from the field of slower parasite clearance rates during drug treatment are generating concern that the useful lifespan of these drugs may be limited. Whether slower clearance rates represent true resistance, and how this provides a selective advantage for parasites is uncertain. Here, we show that Plasmodium chabaudi malaria parasites selected for resistance to artesunate (an artemisinin derivative) through a step-wise increase in drug dose evolved slower clearance rates extremely rapidly. In single infections, these slower clearance rates, similar to those seen in the field, provided fitness advantages to the parasite through increased overall density, recrudescence after treatment and increased transmission potential. In mixed infections, removal of susceptible parasites by drug treatment led to substantial increases in the densities and transmission potential of resistant parasites (competitive release). Our results demonstrate the double-edged sword for resistance management: in our initial selection experiments, no parasites survived aggressive chemotherapy, but after selection, the fitness advantage for resistant parasites was greatest at high drug doses. Aggressive treatment of mixed infections resulted in resistant parasites dominating the pool of gametocytes, without providing additional health benefits to hosts. Slower clearance rates can evolve rapidly and can provide a strong fitness advantage during drug treatment in both single and mixed strain infections. The evolution of drug resistance is a major challenge facing medicine in the 21st century. In the case of malaria parasites, this is particularly apparent, as the introduction of each drug has been followed by the rapid development and spread of resistant parasites. Without a constant supply of new drugs to replace those that are no longer effective, it is important to understand the processes that lead to the selection and spread of resistance though a parasite population, so that the useful lifespan of current drugs can be maximized. Here, we use a rodent malaria model system to try to select for reduced susceptibility to the current frontline malaria drug, artemisinin. We then examine the growth and transmission potential of resistant parasites in single infections and in competition with susceptible parasites (mixed infections) in drug-treated hosts. We show that parasites selected for reduced susceptibility to drugs have increased fitness in both situations. Our results also indicate that the consequences of different treatment regimes on the rate of spread of resistance should be evaluated and taken into account during regime choice.
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影响因子：
2.4
作者：
CARTER, R
通讯作者：
CARTER, R
影响因子：
15.8
作者：
Carrara VI;Lwin KM;Phyo AP;Ashley E;Wiladphaingern J;Sriprawat K;Rijken M;Boel M;McGready R;Proux S;Chu C;Singhasivanon P;White N;Nosten F
通讯作者：
Nosten F
DOI：
10.1073/pnas.0500078102
发表时间：
2005-05-24
影响因子：
11.1
作者：
de Roode, JC;Pansini, R;Read, AF
通讯作者：
Read, AF
DOI：
10.1098/rspb.2010.0196
发表时间：
2010-08-22
期刊：
Proceedings. Biological sciences
影响因子：
--
作者：
Anderson TJ;Williams JT;Nair S;Sudimack D;Barends M;Jaidee A;Price RN;Nosten F
通讯作者：
Nosten F
影响因子：
4.9
作者：
Afonso, A;Hunt, P;Cravo, P
通讯作者：
Cravo, P