Partner-Drug Resistance and Population Substructuring of Artemisinin-Resistant Plasmodium falciparum in Cambodia.
Partner-Drug Resistance and Population Substructuring of Artemisinin-Resistant Plasmodium falciparum in Cambodia.
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DOI：
10.1093/gbe/evx126
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发表时间：
2017-06-01
影响因子：
3.3
通讯作者：
Juliano JJ
中科院分区：
文献类型：
--
作者：
Parobek CM;Parr JB;Brazeau NF;Lon C;Chaorattanakawee S;Gosi P;Barnett EJ;Norris LD;Meshnick SR;Spring MD;Lanteri CA;Bailey JA;Saunders DL;Lin JT;Juliano JJ
柬埔寨西部的恶性疟原虫对青蒿素及其伙伴药物产生了抗药性，导致治疗经常失败。了解这种演变可以为新疗法的部署提供信息。我们使用全基因组测序研究了78株恶性疟原虫分离株的遗传结构，将结果与体内和体外耐药性相关联，并探索了人口结构、人口统计学史和伴侣耐药性之间的关系。主成分分析、网络分析和人口统计推断确定了一个多样化的中心人群，其中有三组克隆扩张的寄生虫种群，每一组都与特定的K13青蒿素耐药等位基因和伙伴药物耐药性特征相关，这与该区域青蒿素综合疗法的顺序部署一致。一个簇显示出离体哌喹耐药性和甲氟喹敏感性，其中二氢青蒿素-哌喹的体内失败率较高。另一个簇显示出离体甲氟喹耐药性和哌喹敏感性，并且双氢青蒿素-哌喹的体内功效很高。最后一个簇是克隆的，对两种药物都表现出中等敏感性。最近描述的哌喹耐药标志物的变化不能解释高和中等哌喹耐药组之间的平均IC 90或临床失败的差异，这表明其他位点可能参与耐药。结果强调了伴侣耐药性在塑造东南亚恶性疟原虫遗传格局中的重要作用，并表明需要进一步的工作来评估其他驱动哌喹耐药性的突变。
Plasmodium falciparum in western Cambodia has developed resistance to artemisinin and its partner drugs, causing frequent treatment failure. Understanding this evolution can inform the deployment of new therapies. We investigated the genetic architecture of 78 falciparum isolates using whole-genome sequencing, correlating results to in vivo and ex vivo drug resistance and exploring the relationship between population structure, demographic history, and partner drug resistance. Principle component analysis, network analysis and demographic inference identified a diverse central population with three clusters of clonally expanding parasite populations, each associated with specific K13 artemisinin resistance alleles and partner drug resistance profiles which were consistent with the sequential deployment of artemisinin combination therapies in the region. One cluster displayed ex vivo piperaquine resistance and mefloquine sensitivity with a high rate of in vivo failure of dihydroartemisinin-piperaquine. Another cluster displayed ex vivo mefloquine resistance and piperaquine sensitivity with high in vivo efficacy of dihydroartemisinin-piperaquine. The final cluster was clonal and displayed intermediate sensitivity to both drugs. Variations in recently described piperaquine resistance markers did not explain the difference in mean IC90 or clinical failures between the high and intermediate piperaquine resistance groups, suggesting additional loci may be involved in resistance. The results highlight an important role for partner drug resistance in shaping the P. falciparum genetic landscape in Southeast Asia and suggest that further work is needed to evaluate for other mutations that drive piperaquine resistance.
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影响因子：
4.5
作者：
Gutenkunst RN;Hernandez RD;Williamson SH;Bustamante CD
通讯作者：
Bustamante CD
与柬埔寨恶性疟原虫疟疾双氢青蒿素-哌喹失败相关的遗传标记：基因型-表型关联研究。
DOI：
10.1016/s1473-3099(16)30409-1
发表时间：
2017-03
期刊：
The Lancet. Infectious diseases
影响因子：
--
作者：
Amato R;Lim P;Miotto O;Amaratunga C;Dek D;Pearson RD;Almagro-Garcia J;Neal AT;Sreng S;Suon S;Drury E;Jyothi D;Stalker J;Kwiatkowski DP;Fairhurst RM
通讯作者：
Fairhurst RM
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
12.3
作者：
Cerqueira GC;Cheeseman IH;Schaffner SF;Nair S;McDew-White M;Phyo AP;Ashley EA;Melnikov A;Rogov P;Birren BW;Nosten F;Anderson TJC;Neafsey DE
通讯作者：
Neafsey DE
影响因子：
5.8
作者：
Jombart, Thibaut;Ahmed, Ismail
通讯作者：
Ahmed, Ismail