Abstract：
Efficacy of sulfadoxine-pyrimethamine, the malaria chemoprophylaxis used in pregnant women, and in children when combined with amodiaquine, is threatened by the accumulation of mutations in the Plasmodium falciparum dihydropteroate synthase (pfdhps) and dihydrofolate reductase (pfdhfr) genes. Data on the prevalence of resistant alleles in central Africa and the new pfdhps I431V mutation, particularly associated with other mutations to form the pfdhps vagKgs allele, are scarce. We explored the frequency and geographical distribution of pfdhps and pfdhfr mutations in central Africa in 2014-18, and assessed the evolutionary origin of the vagKgs allele.
Samples were collected at 18 health-care centres in seven countries (Angola, Cameroon, Central African Republic, Democratic Republic of the Congo, Gabon, Nigeria, and Republic of the Congo) from patients who showed possible symptoms of malaria between March 1, 2014, and Oct 31, 2018. Samples that were positive for P falciparum were transported to a laboratory in Toulouse, France, and genotyped. The frequency of pfdhfr and pfdhps mutations was studied in 1749 samples. Microsatellites in pfdhps flanking regions and whole-genome analysis compared with parasite genomes from the data-sharing network MalariaGEN were performed on samples carrying the vagKgs allele.
Mapping of the prevalence of single nucleotide polymorphisms and corresponding alleles of pfdhfr and pfdhps showed a substantial spread of alleles associated with sulfadoxine-pyrimethamine resistance in central Africa during the 2014-18 period, especially an increase going west to east in pfdhps alleles carrying the K540E and A581G mutations. A high prevalence of the pfdhps I431V mutation was observed in Cameroon (exceeding 50% in the northern region) and Nigeria. Genomic analysis showed a recent African emergence and a clonal expansion of the most frequent pfdhps vagKgs allele.
Reduced sulfadoxine-pyrimethamine efficacy due to increased resistance is a worrying situation, especially because the malaria transmission level is high in central Africa. Although the resistance phenotype remains to be confirmed, the emergence and spread of the vagKgs allele in west and central Africa could challenge the use of sulfadoxine-pyrimethamine.
Toulouse Institute for Infectious and Inflammatory Diseases.
Samples were collected at 18 health-care centres in seven countries (Angola, Cameroon, Central African Republic, Democratic Republic of the Congo, Gabon, Nigeria, and Republic of the Congo) from patients who showed possible symptoms of malaria between March 1, 2014, and Oct 31, 2018. Samples that were positive for P falciparum were transported to a laboratory in Toulouse, France, and genotyped. The frequency of pfdhfr and pfdhps mutations was studied in 1749 samples. Microsatellites in pfdhps flanking regions and whole-genome analysis compared with parasite genomes from the data-sharing network MalariaGEN were performed on samples carrying the vagKgs allele.
Mapping of the prevalence of single nucleotide polymorphisms and corresponding alleles of pfdhfr and pfdhps showed a substantial spread of alleles associated with sulfadoxine-pyrimethamine resistance in central Africa during the 2014-18 period, especially an increase going west to east in pfdhps alleles carrying the K540E and A581G mutations. A high prevalence of the pfdhps I431V mutation was observed in Cameroon (exceeding 50% in the northern region) and Nigeria. Genomic analysis showed a recent African emergence and a clonal expansion of the most frequent pfdhps vagKgs allele.
Reduced sulfadoxine-pyrimethamine efficacy due to increased resistance is a worrying situation, especially because the malaria transmission level is high in central Africa. Although the resistance phenotype remains to be confirmed, the emergence and spread of the vagKgs allele in west and central Africa could challenge the use of sulfadoxine-pyrimethamine.
Toulouse Institute for Infectious and Inflammatory Diseases.
摘要：
背景：磺胺多辛-乙胺嘧啶的疗效，用于孕妇的疟疾化学预防，在儿童中，当与阿莫地喹结合时，受到恶性疟原虫二氢蝶呤合酶（pfdhps）和二氢叶酸还原酶（pfdhfr）基因突变积累的威胁。有关中部非洲耐药等位基因流行率和新的pfdhpsI431V突变的数据，特别是与形成pfdhpsvagKgs等位基因的其他突变相关，是稀缺的。我们探索了2014-18年中非pfdhps和pfdhfr突变的频率和地理分布，并评估了vagKgs等位基因的进化起源。
方法：在七个国家（安哥拉，喀麦隆,中非共和国,刚果民主共和国,加蓬,尼日利亚,和刚果共和国）来自2014年3月1日至2018年10月31日之间表现出可能的疟疾症状的患者。对恶性疟原虫呈阳性的样品被运送到图卢兹的实验室，法国,并进行基因分型。在1749个样品中研究了pfdhfr和pfdhps突变的频率。对携带vagKgs等位基因的样品进行了pfdhps侧翼区的微卫星和与来自数据共享网络MalariaGEN的寄生虫基因组相比的全基因组分析。
结果：对pfdhfr和pfdhps的单核苷酸多态性和相应等位基因的患病率进行的定位显示，在2014-18年期间，与磺胺多辛-乙胺嘧啶耐药相关的等位基因在中部非洲大量扩散，尤其是携带K540E和A581G突变的pfdhps等位基因从西向东增加。在喀麦隆（北部地区超过50％）和尼日利亚观察到pfdhpsI431V突变的高患病率。基因组分析表明，最近在非洲出现，并且最常见的pfdhpsvagKgs等位基因克隆扩增。
结论：由于耐药性增加而导致的磺胺多辛-乙胺嘧啶疗效降低令人担忧，特别是因为中部非洲的疟疾传播水平很高。虽然抗性表型还有待证实,vagKgs等位基因在西非和中非的出现和传播可能对磺胺多辛-乙胺嘧啶的使用提出挑战.
背景：图卢兹传染病和炎症性疾病研究所。
方法：在七个国家（安哥拉，喀麦隆,中非共和国,刚果民主共和国,加蓬,尼日利亚,和刚果共和国）来自2014年3月1日至2018年10月31日之间表现出可能的疟疾症状的患者。对恶性疟原虫呈阳性的样品被运送到图卢兹的实验室，法国,并进行基因分型。在1749个样品中研究了pfdhfr和pfdhps突变的频率。对携带vagKgs等位基因的样品进行了pfdhps侧翼区的微卫星和与来自数据共享网络MalariaGEN的寄生虫基因组相比的全基因组分析。
结果：对pfdhfr和pfdhps的单核苷酸多态性和相应等位基因的患病率进行的定位显示，在2014-18年期间，与磺胺多辛-乙胺嘧啶耐药相关的等位基因在中部非洲大量扩散，尤其是携带K540E和A581G突变的pfdhps等位基因从西向东增加。在喀麦隆（北部地区超过50％）和尼日利亚观察到pfdhpsI431V突变的高患病率。基因组分析表明，最近在非洲出现，并且最常见的pfdhpsvagKgs等位基因克隆扩增。
结论：由于耐药性增加而导致的磺胺多辛-乙胺嘧啶疗效降低令人担忧，特别是因为中部非洲的疟疾传播水平很高。虽然抗性表型还有待证实,vagKgs等位基因在西非和中非的出现和传播可能对磺胺多辛-乙胺嘧啶的使用提出挑战.
背景：图卢兹传染病和炎症性疾病研究所。
