Imwong Mallika, Suwannasin Kanokon, Kunasol Chanon, Sutawong Kreepol, Mayxay Mayfong, Rekol Huy, Smithuis Frank M, Hlaing Tin Maung, Tun Kyaw M, van der Pluijm Rob W, Tripura Rupam, Miotto Olivo, Menard Didier, Dhorda Mehul, Day Nicholas P J, White Nicholas J, Dondorp Arjen M
Department of Molecular Tropical Medicine and Genetics, Mahidol University, Bangkok, Thailand; Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Lancet Infect Dis. 2017 May;17(5):491-497. doi: 10.1016/S1473-3099(17)30048-8. Epub 2017 Feb 2.
Evidence suggests that the PfKelch13 mutations that confer artemisinin resistance in falciparum malaria have multiple independent origins across the Greater Mekong subregion, which has motivated a regional malaria elimination agenda. We aimed to use molecular genotyping to assess antimalarial drug resistance selection and spread in the Greater Mekong subregion.
In this observational study, we tested Plasmodium falciparum isolates from Myanmar, northeastern Thailand, southern Laos, and western Cambodia for PfKelch13 mutations and for Pfplasmepsin2 gene amplification (indicating piperaquine resistance). We collected blood spots from patients with microscopy or rapid test confirmed uncomplicated falciparum malaria. We used microsatellite genotyping to assess genetic relatedness.
As part of studies on the epidemiology of artemisinin-resistant malaria between Jan 1, 2008, and Dec 31, 2015, we collected 434 isolates. In 2014-15, a single long PfKelch13 C580Y haplotype (-50 to +31·5 kb) lineage, which emerged in western Cambodia in 2008, was detected in 65 of 88 isolates from northeastern Thailand, 86 of 111 isolates from southern Laos, and 14 of 14 isolates from western Cambodia, signifying a hard transnational selective sweep. Pfplasmepsin2 amplification occurred only within this lineage, and by 2015 these closely related parasites were found in ten of the 14 isolates from Cambodia and 15 of 15 isolates from northeastern Thailand. C580Y mutated parasites from Myanmar had a different genetic origin.
Our results suggest that the dominant artemisinin-resistant P falciparum C580Y lineage probably arose in western Cambodia and then spread to Thailand and Laos, outcompeting other parasites and acquiring piperaquine resistance. The emergence and spread of fit artemisinin-resistant P falciparum parasite lineages, which then acquire partner drug resistance across the Greater Mekong subregion, threatens regional malaria control and elimination goals. Elimination of falciparum malaria from this region should be accelerated while available antimalarial drugs still remain effective.
The Wellcome Trust and the Bill and Melinda Gates Foundation.
有证据表明，恶性疟原虫中导致青蒿素耐药性的PfKelch13突变在大湄公河次区域有多个独立起源，这推动了一项区域疟疾消除议程。我们旨在利用分子基因分型来评估抗疟药物耐药性的选择和在大湄公河次区域的传播情况。
在这项观察性研究中，我们对来自缅甸、泰国东北部、老挝南部和柬埔寨西部的恶性疟原虫分离株进行了PfKelch13突变和Pfplasmepsin2基因扩增检测（表明对双氢青蒿素哌喹耐药）。我们从经显微镜检查或快速检测确诊为非复杂性恶性疟的患者身上采集血斑。我们使用微卫星基因分型来评估遗传相关性。
作为2008年1月1日至2015年12月31日期间青蒿素耐药性疟疾流行病学研究的一部分，我们收集了434株分离株。在2014 - 2015年，一个单一的长PfKelch13 C580Y单倍型（-50至+31.5 kb）谱系（2008年出现在柬埔寨西部）在泰国东北部88株分离株中的65株、老挝南部111株分离株中的86株以及柬埔寨西部14株分离株中的14株中被检测到，这表明存在一次强烈的跨国选择性清除。Pfplasmepsin2扩增仅发生在该谱系内，到2015年，在柬埔寨14株分离株中的10株以及泰国东北部15株分离株中的15株中发现了这些密切相关的寄生虫。来自缅甸的C580Y突变寄生虫有不同的遗传起源。
我们的结果表明，占主导地位的对青蒿素耐药的恶性疟原虫C580Y谱系可能起源于柬埔寨西部，然后传播到泰国和老挝，取代了其他寄生虫并获得了对双氢青蒿素哌喹的耐药性。适应性强的对青蒿素耐药的恶性疟原虫谱系的出现和传播，随后在大湄公河次区域获得对联合用药的耐药性，威胁到区域疟疾控制和消除目标。在现有抗疟药物仍然有效的情况下，应加快从该区域消除恶性疟。
惠康信托基金会和比尔及梅琳达·盖茨基金会。
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