Artemisinin resistance without pfkelch13 mutations in Plasmodium falciparum isolates from Cambodia.
Artemisinin resistance without pfkelch13 mutations in Plasmodium falciparum isolates from Cambodia.
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DOI：
10.1186/s12936-017-1845-5
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发表时间：
2017-05-12
期刊：
影响因子：
3
通讯作者：
Volkman SK
中科院分区：
文献类型：
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作者：
Mukherjee A;Bopp S;Magistrado P;Wong W;Daniels R;Demas A;Schaffner S;Amaratunga C;Lim P;Dhorda M;Miotto O;Woodrow C;Ashley EA;Dondorp AM;White NJ;Wirth D;Fairhurst R;Volkman SK
青蒿素耐药性与体内寄生虫清除半衰期延迟有关，并与体外双氢青蒿素作用下的环期存活相关。这两种表型都与PF3D7_1343700 PfKelch13基因突变有关。最近青蒿素耐药性和新出现的哌喹耐药性在东南亚的蔓延表明，青蒿素联合疗法，如双氢青蒿素-哌喹，正在失去临床疗效，促使人们研究耐药机制，并制定克服新出现的抗疟疾耐药性的策略。从柬埔寨的两个青蒿素耐药性跟踪合作研究地点获得了68株具有体内清除数据的寄生虫分离物，经培养适应，并对PfKelch13和其他突变(包括pfmdr1拷贝数)进行了基因分型；并测量了其中36株分离物的RSA0-3h存活率和对抗疟疾药物的体外反应。在这36种寄生虫中，有一株显示PfKelch13突变(D584V，RSA0-3h)的环期存活率增加，以前与清除缓慢有关，但尚未在体外进行测试。几种寄生虫表现出环期存活率增加，但缺乏PfKelch13突变，一种分离物显示出哌喹耐药性的证据。这项研究对柬埔寨68个已知清除值的恶性疟原虫临床分离株进行了研究，发现D584V PfKelch13突变与环期存活率增加有关，并确定了缺乏PfKelch13突变但表现出环期存活率增加的寄生虫。这些数据表明，PfKelch13中发现的突变可能参与了恶性疟原虫对青蒿素的抗药性。在同样的柬埔寨样本中也检测到了哌喹耐药性，这与现场出现哌喹耐药性的报告一致。这些适应培养的寄生虫允许进一步研究青蒿素和哌喹耐药性的机制，并制定预防或克服抗疟疾耐药性的策略。本文的在线版本(doi：10.1186/s12936-0171845-5)包含补充材料，授权用户可以使用。
Artemisinin resistance is associated with delayed parasite clearance half-life in vivo and correlates with ring-stage survival under dihydroartemisinin in vitro. Both phenotypes are associated with mutations in the PF3D7_1343700 pfkelch13 gene. Recent spread of artemisinin resistance and emerging piperaquine resistance in Southeast Asia show that artemisinin combination therapy, such as dihydroartemisinin–piperaquine, are losing clinical effectiveness, prompting investigation of drug resistance mechanisms and development of strategies to surmount emerging anti-malarial resistance. Sixty-eight parasites isolates with in vivo clearance data were obtained from two Tracking Resistance to Artemisinin Collaboration study sites in Cambodia, culture-adapted, and genotyped for pfkelch13 and other mutations including pfmdr1 copy number; and the RSA0–3h survival rates and response to antimalarial drugs in vitro were measured for 36 of these isolates. Among these 36 parasites one isolate demonstrated increased ring-stage survival for a PfKelch13 mutation (D584V, RSA0–3h = 8%), previously associated with slow clearance but not yet tested in vitro. Several parasites exhibited increased ring-stage survival, yet lack pfkelch13 mutations, and one isolate showed evidence for piperaquine resistance. This study of 68 culture-adapted Plasmodium falciparum clinical isolates from Cambodia with known clearance values, associated the D584V PfKelch13 mutation with increased ring-stage survival and identified parasites that lack pfkelch13 mutations yet exhibit increased ring-stage survival. These data suggest mutations other than those found in pfkelch13 may be involved in conferring artemisinin resistance in P. falciparum. Piperaquine resistance was also detected among the same Cambodian samples, consistent with reports of emerging piperaquine resistance in the field. These culture-adapted parasites permit further investigation of mechanisms of both artemisinin and piperaquine resistance and development of strategies to prevent or overcome anti-malarial resistance. The online version of this article (doi:10.1186/s12936-017-1845-5) contains supplementary material, which is available to authorized users.