评估来自毛里塔尼亚的间日疟原虫分离株的耐药相关遗传多样性揭示了有限的多态性。
Assessment of drug resistance associated genetic diversity in Mauritanian isolates of Plasmodium vivax reveals limited polymorphism.
机构信息
Unité de Recherche Génome et Milieux (JEAI), Faculté des Sciences et Techniques, Université de Nouakchott Al-Aasriya, Nouveau campus universitaire, BP 5026, Nouakchott, Mauritania.
Unité Mixte de Recherche 216 Mère et enfant face aux infections tropicales, Institut de Recherche pour le Développement (IRD), Faculté de Pharmacie, Université Paris Descartes, 4 avenue de l'Observatoire, 75270, Paris Cedex 06, France.
出版信息
Malar J. 2018 Nov 8;17(1):416. doi: 10.1186/s12936-018-2548-2.
BACKGROUND
Plasmodium vivax is the predominant malaria species in northern Mauritania. Molecular data on P. vivax isolates circulating in West Africa are scarce. The present study analysed molecular markers associated with resistance to antifolates (Pvdhfr and Pvdhps), chloroquine (Pvmdr1), and artemisinin (Pvk12) in P. vivax isolates collected in two cities located in the Saharan zone of Mauritania.
METHODS
Blood samples were obtained from P. vivax-infected patients recruited for chloroquine therapeutic efficacy study in 2013 and febrile patients spontaneously consulting health facilities in Nouakchott and Atar in 2015-2016. Fragments of Pvdhfr (codons 13, 33, 57, 58, 61, 117, and 174), Pvdhps (codons 382, 383, 512, 553, and 585), Pvmdr1 (codons 976 and 1076) and Pvk12 (codon 552) genes were amplified by PCR and sequenced.
RESULTS
Most of the isolates in Nouakchott (126/154, 81.8%) and Atar (44/45, 97.8%) carried the wild-type Pvdhfr allelic variant (IPFSTSI). In Nouakchott, all mutants (28/154; 18.2%) had double Pvdhfr mutations in positions 58 and 61 (allelic variant IPFRMSI), whereas in Atar only 1 isolate was mutant (S117N, allelic variant IPFSTNI). The wild-type Pvdhps allelic variant (SAKAV) was found in all tested isolates (Nouakchott, n = 93; Atar, n = 37). Few isolates in Nouakchott (5/115, 4.3%) and Atar (3/79, 3.8%) had the mutant Pvmdr1 allele 976F or 1076L, but not both, including in pre-treatment isolates obtained from patients treated successfully with chloroquine. All isolates (59 in Nouakchott and 48 in Atar) carried the wild-type V552 allele in Pvk12.
CONCLUSIONS
Polymorphisms in Pvdhfr, Pvdhps, Pvmdr1, and Pvk12 were limited in P. vivax isolates collected recently in Nouakchott and Atar. Compared to the isolates collected in Nouakchott in 2007-2009, there was no evidence for selection of mutants. The presence of one, but not both, of the two potential markers of chloroquine resistance in Pvmdr1 in pre-treatment isolates did not influence the clinical outcome, putting into question the role of Pvmdr1 mutant alleles 976F and 1076L in treatment failure. Molecular surveillance is an important component of P. vivax malaria control programme in the Saharan zone of Mauritania to predict possible emergence of drug-resistant parasites.
背景
间日疟原虫是毛里塔尼亚北部主要的疟疾寄生虫。关于在西非循环的间日疟原虫分离株的分子数据很少。本研究分析了与抗叶酸药物（Pvdhfr 和 Pvdhps）、氯喹（Pvmdr1）和青蒿素（Pvk12）耐药性相关的分子标记，这些标记在 2013 年采集自毛里塔尼亚撒哈拉地区两个城市的感染间日疟原虫的患者血液样本中发现。
方法
从 2013 年接受氯喹疗效治疗研究的间日疟原虫感染患者和 2015 年至 2016 年在努瓦克肖特和阿塔尔自发就诊的发热患者中采集血液样本。通过 PCR 扩增和测序，分析了 Pvdhfr（密码子 13、33、57、58、61、117 和 174）、Pvdhps（密码子 382、383、512、553 和 585）、Pvmdr1（密码子 976 和 1076）和 Pvk12（密码子 552）基因的片段。
结果
努瓦克肖特（126/154，81.8%）和阿塔尔（44/45，97.8%）的大多数分离株均携带野生型 Pvdhfr 等位基因变异体（IPFSTSI）。在努瓦克肖特，所有突变体（28/154；18.2%）在位置 58 和 61 处均具有双重 Pvdhfr 突变（等位基因变异体 IPFRMSI），而在阿塔尔仅有 1 个分离株发生突变（S117N，等位基因变异体 IPFSTNI）。所有检测到的分离株（努瓦克肖特，n=93；阿塔尔，n=37）均携带野生型 Pvdhps 等位基因变异体（SAKAV）。努瓦克肖特（5/115，4.3%）和阿塔尔（3/79，3.8%）的少数分离株具有突变型 Pvmdr1 等位基因 976F 或 1076L，但不是两者都有，包括用氯喹成功治疗的患者的治疗前分离株。所有分离株（努瓦克肖特 59 株，阿塔尔 48 株）在 Pvk12 中携带野生型 V552 等位基因。
结论
最近在努瓦克肖特和阿塔尔采集的间日疟原虫分离株中，Pvdhfr、Pvdhps、Pvmdr1 和 Pvk12 中的多态性有限。与 2007-2009 年在努瓦克肖特采集的分离株相比，没有证据表明存在突变体的选择。在治疗前分离株中，Pvmdr1 中只有一个而不是两个潜在的氯喹耐药标记物的存在并不影响临床结局，这使 Pvmdr1 突变等位基因 976F 和 1076L 在治疗失败中的作用受到质疑。分子监测是毛里塔尼亚撒哈拉地区间日疟原虫疟疾控制计划的重要组成部分，可预测可能出现的耐药寄生虫。
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