Kim Yuseob, Escalante Ananias A, Schneider Kristan A
Department of Life Science and Division of EcoScience, Ewha Womans University, Seoul, South Korea.
School of Life Sciences and Center for Evolutionary Medicine and Informatics at the Biodesign Institute, Arizona State University, Tempe, Arizona, United States of America.
PLoS One. 2014 Jul 9;9(7):e101601. doi: 10.1371/journal.pone.0101601. eCollection 2014.
To develop public-health policies that extend the lifespan of affordable anti-malarial drugs as effective treatment options, it is necessary to understand the evolutionary processes leading to the origin and spread of mutations conferring drug resistance in malarial parasites. We built a population-genetic model for the emergence of resistance under combination drug therapy. Reproductive cycles of parasites are specified by their absolute fitness determined by clinical parameters, thus coupling the evolutionary-genetic with population-dynamic processes. Initial mutations confer only partial drug-resistance. Therefore, mutant parasites rarely survive combination therapy and within-host competition is very weak among parasites. The model focuses on the early phase of such unsuccessful recurrent mutations. This ends in the rare event of mutants enriching in an infected individual from which the successful spread of resistance over the entire population is initiated. By computer simulations, the waiting time until the establishment of resistant parasites is analysed. Resistance spreads quickly following the first appearance of a host infected predominantly by mutant parasites. This occurs either through a rare transmission of a resistant parasite to an uninfected host or through a rare failure of drugs in removing "transient" mutant alleles. The emergence of resistance is delayed with lower mutation rate, earlier treatment, higher metabolic cost of resistance, longer duration of high drug dose, and higher drug efficacy causing a stronger reduction in the sensitive and resistant parasites' fitnesses. Overall, contrary to other studies' proposition, the current model based on absolute fitness suggests that aggressive drug treatment delays the emergence of drug resistance.
为制定公共卫生政策，将价格亲民的抗疟药物的使用寿命延长为有效的治疗选择，有必要了解导致疟原虫产生耐药性突变的起源和传播的进化过程。我们构建了一个联合药物治疗下耐药性出现的群体遗传模型。寄生虫的生殖周期由临床参数决定的绝对适合度来指定，从而将进化遗传学与群体动态过程联系起来。初始突变仅赋予部分耐药性。因此，突变寄生虫在联合治疗中很少存活，且宿主内寄生虫之间的竞争非常微弱。该模型关注的是这种反复出现的不成功突变的早期阶段。这以突变体在受感染个体中富集这一罕见事件告终，由此开启了耐药性在整个人口中的成功传播。通过计算机模拟，分析了耐药寄生虫建立之前的等待时间。在主要由突变寄生虫感染的宿主首次出现后，耐药性迅速传播。这要么是通过耐药寄生虫向未感染宿主的罕见传播，要么是通过药物清除“短暂”突变等位基因的罕见失败。随着突变率降低、治疗提前、耐药的代谢成本增加、高剂量药物持续时间延长以及药物疗效提高导致敏感和耐药寄生虫的适合度更强降低，耐药性的出现会延迟。总体而言，与其他研究的观点相反，基于绝对适合度的当前模型表明积极的药物治疗会延迟耐药性的出现。
