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青蒿素联合疗法引入前后赤道几内亚大陆地区恶性疟原虫的遗传多样性

Plasmodium falciparum Genetic Diversity in Continental Equatorial Guinea before and after Introduction of Artemisinin-Based Combination Therapy.

作者信息

Guerra Mónica, Neres Rita, Salgueiro Patrícia, Mendes Cristina, Ndong-Mabale Nicolas, Berzosa Pedro, de Sousa Bruno, Arez Ana Paula

机构信息

Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa (UNL), Lisbon, Portugal.

Centro de Referencia para el Control de Endemias, Instituto de Salud Carlos III, Bata, Equatorial Guinea.

出版信息

Antimicrob Agents Chemother. 2016 Dec 27;61(1). doi: 10.1128/AAC.02556-15. Print 2017 Jan.

Abstract

Efforts to control malaria may affect malaria parasite genetic variability and drug resistance, the latter of which is associated with genetic events that promote mechanisms to escape drug action. The worldwide spread of drug resistance has been a major obstacle to controlling Plasmodium falciparum malaria, and thus the study of the origin and spread of associated mutations may provide some insights into the prevention of its emergence. This study reports an analysis of P. falciparum genetic diversity, focusing on antimalarial resistance-associated molecular markers in two socioeconomically different villages in mainland Equatorial Guinea. The present study took place 8 years after a previous one, allowing the analysis of results before and after the introduction of an artemisinin-based combination therapy (ACT), i.e., artesunate plus amodiaquine. Genetic diversity was assessed by analysis of the Pfmsp2 gene and neutral microsatellite loci. Pfdhps and Pfdhfr alleles associated with sulfadoxine-pyrimethamine (SP) resistance and flanking microsatellite loci were investigated, and the prevalences of drug resistance-associated point mutations of the Pfcrt, Pfmdr1, Pfdhfr, and Pfdhps genes were estimated. Further, to monitor the use of ACT, we provide the baseline prevalences of K13 propeller mutations and Pfmdr1 copy numbers. After 8 years, noticeable differences occurred in the distribution of genotypes conferring resistance to chloroquine and SP, and the spread of mutated genotypes differed according to the setting. Regarding artemisinin resistance, although mutations reported as being linked to artemisinin resistance were not present at the time, several single nucleotide polymorphisms (SNPs) were observed in the K13 gene, suggesting that closer monitoring should be maintained to prevent the possible spread of artemisinin resistance in Africa.

摘要

控制疟疾的努力可能会影响疟原虫的遗传变异性和耐药性,后者与促进逃避药物作用机制的遗传事件有关。耐药性在全球范围内的传播一直是控制恶性疟原虫疟疾的主要障碍,因此对相关突变的起源和传播进行研究可能会为预防其出现提供一些见解。本研究报告了对恶性疟原虫遗传多样性的分析,重点关注赤道几内亚大陆两个社会经济状况不同的村庄中与抗疟药耐药性相关的分子标记。本研究在之前一项研究的8年后开展,从而能够分析引入以青蒿素为基础的联合疗法(ACT)(即青蒿琥酯加阿莫地喹)前后的结果。通过分析Pfmsp2基因和中性微卫星位点评估遗传多样性。研究了与磺胺多辛-乙胺嘧啶(SP)耐药性相关的Pfdhps和Pfdhfr等位基因及其侧翼微卫星位点,并估计了Pfcrt、Pfmdr1、Pfdhfr和Pfdhps基因耐药性相关点突变的流行率。此外,为监测ACT的使用情况,我们提供了K13螺旋桨突变和Pfmdr1拷贝数的基线流行率。8年后,对氯喹和SP耐药的基因型分布出现了显著差异,且突变基因型的传播因环境而异。关于青蒿素耐药性,尽管当时未发现报告与青蒿素耐药性相关的突变,但在K13基因中观察到了几个单核苷酸多态性(SNP),这表明应持续进行更密切的监测,以防止青蒿素耐药性在非洲可能的传播。

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