Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, Tokyo, Japan.
J Infect Dis. 2014 Jan 1;209(1):130-9. doi: 10.1093/infdis/jit415. Epub 2013 Aug 6.
Monitoring the prevalence of drug resistant Plasmodium falciparum is essential for effective malaria control. Resistance to pyrimethamine and sulfadoxine increases as mutations accumulate in the parasite genes encoding dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps), respectively. Although parasites are exposed to these antifolate drugs simultaneously, it remains virtually unknown whether dhfr and dhps mutations accumulate along interrelated paths.
We investigated the order of step-wise accumulation in dhfr and dhps by cumulative analyses using binomial tests in 575 P. falciparum isolates obtained from 7 countries in Asia and Melanesia.
An initial step in the accumulation of mutations preferentially occurred in dhfr (2 mutations), followed by 1 mutation in dhps. In a subsequent step, mutations were estimated separately for 5 dhfr/dhps-resistant lineages identified using 12 microsatellites flanking dhfr and dhps. Among these lineages, we found 3 major mutational paths, each of which follows a unique stepwise trajectory to produce the most highly resistant form with 4 mutations in dhfr and 3 in dhps.
The ordered accumulation of mutations in dhfr and dhps elucidated here will assist in predicting the status and progression of antifolate resistance in malaria-endemic regions where antifolate drugs are used for intermittent preventive treatment.
监测耐疟原虫恶性疟的流行情况对于有效控制疟疾至关重要。随着寄生虫基因中编码二氢叶酸还原酶（dhfr）和二氢蝶酸合成酶（dhps）的突变积累，对氨苯砜和乙胺嘧啶的耐药性分别增加。尽管寄生虫同时接触这些抗叶酸药物，但实际上仍不清楚 dhfr 和 dhps 突变是否沿着相互关联的途径积累。
我们通过在亚洲和美拉尼西亚 7 个国家获得的 575 株疟原虫分离株中使用二项式检验进行累积分析，研究了 dhfr 和 dhps 中逐步积累的顺序。
突变积累的初始步骤优先发生在 dhfr（2 个突变）中，然后是 dhps 中的 1 个突变。在随后的步骤中，使用 12 个侧翼 dhfr 和 dhps 的微卫星，我们分别估计了 5 种 dhfr/dhps 耐药系中的突变。在这些谱系中，我们发现了 3 种主要的突变途径，每种途径都遵循独特的逐步轨迹，产生最具耐药性的形式，dhfr 中有 4 个突变，dhps 中有 3 个突变。
这里阐明的 dhfr 和 dhps 中突变的有序积累将有助于预测在使用抗叶酸药物进行间歇性预防治疗的疟疾流行地区抗叶酸耐药的状况和进展。
