Plasmodium falciparum dhfr but not dhps mutations associated with sulphadoxine-pyrimethamine treatment failure and gametocyte carriage in northern Ghana
Plasmodium falciparum dhfr but not dhps mutations associated with sulphadoxine-pyrimethamine treatment failure and gametocyte carriage in northern Ghana
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DOI：
10.1111/j.1365-3156.2005.01471.x
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发表时间：
2005-09-01
影响因子：
3.3
通讯作者：
Bienzle, U
中科院分区：
文献类型：
--
作者：
Mockenhaupt, FP;Bousema, JT;Bienzle, U
在撒哈拉以南非洲，磺胺二甲基乙胺(SP)的使用和恶性疟原虫对SP的耐药性都在增加。恶性疟原虫二氢叶酸还原酶(DHFR)和二氢翼酸合成酶(DHPS)基因突变可以预测SP治疗失败，但这种关系的程度因地区而异。在加纳北部，对126名儿童治疗前的dhfr/dhps基因型别进行了检测，并分析了与聚合酶链式反应校正的SP治疗结果和配子体携带的关系。随访4周内SP治疗失败率为28%。DHFR三重突变(Ile-51+Arg-59+ASN-108)在所有治疗前菌株中的检出率为47%。与dhfr野生型寄生虫相比，dhfr三重突变的存在使治疗失败的风险增加了10倍。同样，在存在DHFR变异体的情况下，寄生虫的清除被推迟。治疗失败菌株选用DHfr突变体和DHPs Gly-437。治疗后1周的配子细胞增多症与DHFR突变密切相关。值得注意的是，配子体在招募时的普遍存在也是如此。DHPS等位基因既不影响治疗结果，也不影响配子体携带。在加纳北部，dhfr三重突变的流行可用作筛查和监测SP耐药性的工具。DHPS等位基因与SP治疗结果之间缺乏关联，这表明目前这些分子标记在该地区发挥的作用很小。
Both use of sulphadoxine-pyrimethamine (SP) and SP-resistance of Plasmodium falciparum are increasing in sub-Saharan Africa. Mutations in the P. falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes can predict treatment failure of SP, however, the degree of this relationship varies regionally. In northern Ghana, pre-treatment dhfr/dhps genotypes were examined in 126 children and associations with PCR-corrected SP treatment outcome and gametocyte carriage were analysed. SP treatment failure within 4 weeks of follow-up occurred in 28%. Among all pre-treatment isolates, the dhfr triple mutation (Ile-51 + Arg-59 + Asn-108) was detected in 47%. Compared with dhfr wildtype parasites, the presence of the dhfr triple mutation increased the risk of treatment failure tenfold. Likewise, parasite clearance was delayed in the presence of dhfr variants. Dhfr mutants and dhps Gly-437 were selected in treatment failure isolates. Gametocytaemia 1 week following treatment was strongly associated with dhfr mutations. Remarkably, this was also true for the prevalence of gametocytes at recruitment. Dhps alleles did neither influence treatment outcome nor gametocyte carriage. In northern Ghana, the prevalence of the dhfr triple mutation can be used as a tool to screen for and to monitor SP resistance. The lack of association between dhps alleles and SP treatment outcome suggests a minor role of these molecular markers in this region at present.