Chloroquine clinical failures in P. falciparum malaria are associated with mutant Pfmdr-1, not Pfcrt in Madagascar.
Chloroquine clinical failures in P. falciparum malaria are associated with mutant Pfmdr-1, not Pfcrt in Madagascar.
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DOI：
10.1371/journal.pone.0013281
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发表时间：
2010-10-13
期刊：
影响因子：
3.7
通讯作者：
Ménard D
中科院分区：
文献类型：
--
作者：
Andriantsoanirina V;Ratsimbasoa A;Bouchier C;Tichit M;Jahevitra M;Rabearimanana S;Raherinjafy R;Mercereau-Puijalon O;Durand R;Ménard D
分子生物学研究表明，恶性疟原虫氯喹抗性转运蛋白基因(Pfcrt)突变在氯喹耐药性中起主要作用，而恶性疟原虫多药耐药基因(Pfmdr-1)突变起调节作用。在马达加斯加，氯喹治疗失败率(44%)似乎与体外CQ敏感性(CQ抗药性寄生虫流行率5%)或Pfcrt突变菌株(1%)的总体水平脱节，与撒哈拉以南非洲国家形成强烈对比。以前的研究表明Pfmdr-1突变寄生虫的频率很高(>；60%的分离物)，但没有探索它们与恶性疟原虫氯喹耐药性的关系。为了证明Pfmdr-1等位基因与马达加斯加对氯喹耐药性的关系，对249例恶性疟原虫样本进行了Pfcrt/Pfmdr-1基因分型和Pfmdr-1拷贝数估计。除2株外，其余标本均为野生型Pfcrt等位基因，无Pfmdr-1扩增。氯喹治疗失败与Pfmdr-1 86Y突变密码子(OR = 4.6)显著相关。携带Pfmdr-1 86Y突变的患者在第0天的累积复发发生率(21天)短于携带Pfmdr-1 86N野生型密码子的患者(28天)。在一组独立的90个选定的分离株中，体外对氯喹的敏感性与Pfmdr-1基因的多态无关。对Pfmdr-1等位基因两侧的两个微卫星的分析表明，突变发生在多个遗传背景上。在马达加斯加，Pfmdr-1多态与晚期氯喹临床失败相关，与体外敏感性或Pfcrt基因无关。这些结果突显了目前常规用于监测CQ耐药性的体外试验在这一独特背景下的局限性。了解Pfmdr1基因多态的调节机制仍然很重要，特别是关于Pfmdr-1等位基因在不断变化的药物压力下在恶性疟原虫种群中的进化和传播，这可能在抗疟疾使用管理方面产生重要影响。
Molecular studies have demonstrated that mutations in the Plasmodium falciparum chloroquine resistance transporter gene (Pfcrt) play a major role in chloroquine resistance, while mutations in P. falciparum multidrug resistance gene (Pfmdr-1) act as modulator. In Madagascar, the high rate of chloroquine treatment failure (44%) appears disconnected from the overall level of in vitro CQ susceptibility (prevalence of CQ-resistant parasites <5%) or Pfcrt mutant isolates (<1%), strongly contrasting with sub-Saharan African countries. Previous studies showed a high frequency of Pfmdr-1 mutant parasites (>60% of isolates), but did not explore their association with P. falciparum chloroquine resistance. To document the association of Pfmdr-1 alleles with chloroquine resistance in Madagascar, 249 P. falciparum samples collected from patients enrolled in a chloroquine in vivo efficacy study were genotyped in Pfcrt/Pfmdr-1 genes as well as the estimation of the Pfmdr-1 copy number. Except 2 isolates, all samples displayed a wild-type Pfcrt allele without Pfmdr-1 amplification. Chloroquine treatment failures were significantly associated with Pfmdr-1 86Y mutant codon (OR = 4.6). The cumulative incidence of recurrence of patients carrying the Pfmdr-1 86Y mutation at day 0 (21 days) was shorter than patients carrying Pfmdr-1 86N wild type codon (28 days). In an independent set of 90 selected isolates, in vitro susceptibility to chloroquine was not associated with Pfmdr-1 polymorphisms. Analysis of two microsatellites flanking Pfmdr-1 allele showed that mutations occurred on multiple genetic backgrounds. In Madagascar, Pfmdr-1 polymorphism is associated with late chloroquine clinical failures and unrelated with in vitro susceptibility or Pfcrt genotype. These results highlight the limits of the current in vitro tests routinely used to monitor CQ drug resistance in this unique context. Gaining insight about the mechanisms that regulate polymorphism in Pfmdr1 remains important, particularly regarding the evolution and spread of Pfmdr-1 alleles in P. falciparum populations under changing drug pressure which may have important consequences in terms of antimalarial use management.
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影响因子：
4.9
作者：
Andriantsoanirina, Valerie;Ratsimbasoa, Arsene;Menard, Didier
通讯作者：
Menard, Didier
DOI：
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