首页> 外文期刊>Antimicrobial agents and chemotherapy. >Molecular Determination of Point Mutation Haplotypes in the Dihydrofolate Reductase and Dihydropteroate Synthase of Plasmodium falciparum in Three Districts of Northern Tanzania.
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Molecular Determination of Point Mutation Haplotypes in the Dihydrofolate Reductase and Dihydropteroate Synthase of Plasmodium falciparum in Three Districts of Northern Tanzania.

机译:坦桑尼亚北部三个地区恶性疟原虫二氢叶酸还原酶和二氢蝶呤合酶中点突变单倍型的分子测定。

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摘要

The antimalarial combination of sulfadoxine and pyrimethamine (SP) was introduced as first-line treatment for uncomplicated malaria in Tanzania during 2001 following 18 years of second-line use. The genetic determinants of in vitro resistance to the two drugs individually are shown to be point mutations at seven sites in the dihydrofolate reductase gene (dhfr) conferring resistance to pyrimethamine and five sites in the dihydropteroate synthase (dhps) gene conferring resistance to sulfadoxine. Different combinations of mutations within each gene confer differing degrees of insensitivity, but information about the frequency with which allelic haplotypes occur has been lacking because of the complicating effects of multiple infection. Here we used a novel high-throughput sequence-specific oligonucleotide probe-based approach to examine the present resistance status of three Plasmodium falciparum populations in northern Tanzania. By using surveys of asymptomatic infections and screening for the presence of all known point mutations in dhfr and dhps genes, we showed that just five dhfr and three dhps allelic haplotypes are present. High frequencies of both triple-mutant dhfr and double-mutant dhps mutant alleles were found in addition to significant interregional heterogeneity in allele frequency. In vivo studies have shown that the cooccurrence of three dhfr mutations and two dhps mutations in an infection prior to treatment is statistically predictive of treatment failure. We have combined data for both loci to determine the frequency of two-locus genotypes. The triple-dhfr/double-dhps genotype is present in all three regions with frequencies ranging between 30 and 63%, indicating that treatment failure rates are likely to be high.
机译:磺胺多辛和乙胺嘧啶(SP)的抗疟疾组合在二线使用18年后于2001年引入坦桑尼亚,作为一线治疗简单的疟疾。对两种药物分别具有体外抗药性的遗传决定因素显示为在二氢叶酸还原酶基因(dhfr)中具有对乙胺嘧啶抗性的七个位点和在二氢蝶呤合酶(dhps)基因中具有对磺胺多辛抗性的五个位点的点突变。每个基因中突变的不同组合赋予不同程度的不敏感性,但是由于多重感染的复杂作用,缺乏关于等位基因单倍型发生频率的信息。在这里,我们使用一种新颖的基于高通量序列的寡核苷酸探针为基础的方法来检查坦桑尼亚北部三个恶性疟原虫种群的当前抗药性。通过对无症状感染的调查以及dhfr和dhps基因中所有已知点突变的存在筛选,我们显示仅存在5个dhfr和3个dhps等位基因单倍型。除了在等位基因频率上存在明显的区域间异质性外,还发现了三突变dhfr和双突变dhps突变等位基因的高频率。体内研究表明,治疗前在感染中同时出现三个dhfr突变和两个dhps突变在统计学上可预测治疗失败。我们结合了两个基因座的数据来确定两基因座基因型的频率。在所有三个区域中都存在三倍dhfr /双倍dhps基因型,频率范围在30%到63%之间,表明治疗失败率可能很高。

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