Emergence of artemisinin-resistant Plasmodium falciparum with kelch13 C580Y mutations on the island of New Guinea.
Emergence of artemisinin-resistant Plasmodium falciparum with kelch13 C580Y mutations on the island of New Guinea.
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DOI：
10.1371/journal.ppat.1009133
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发表时间：
2020-12
期刊：
影响因子：
6.7
通讯作者：
Mita T
中科院分区：
文献类型：
--
作者：
Miotto O;Sekihara M;Tachibana SI;Yamauchi M;Pearson RD;Amato R;Gonçalves S;Mehra S;Noviyanti R;Marfurt J;Auburn S;Price RN;Mueller I;Ikeda M;Mori T;Hirai M;Tavul L;Hetzel MW;Laman M;Barry AE;Ringwald P;Ohashi J;Hombhanje F;Kwiatkowski DP;Mita T
携带kelch13基因C580Y突变的青蒿素耐药恶性疟原虫的快速和积极传播对东南亚消除疟疾的威胁越来越大，但没有证据表明它们传播到其他地区。我们于2016年和2017年在巴布亚新几内亚（PNG）Wewak的两个诊所进行了横断面调查，在239份基因分型临床样本中发现了3例由C580 Y突变体引起的感染。其中一个突变体表现出最高的存活率（6.8%）在所有寄生虫调查的环阶段生存测定（RSA）青蒿素。对kelch13侧翼区的分析，以及来自巴布亚新几内亚、印度尼西亚巴布亚和柬埔寨西部的389个临床样本的深度测序数据的比较，表明Wewak C580 Y突变的独立起源，表明突变体具有几个独特的遗传特征。血统同一性（IBD）表明，突变体基因组的多个部分与印度尼西亚巴布亚发现的寄生虫有共同的起源，包括先前与耐药性相关的基因内的几个突变，如mdr1，铁氧还蛋白，atg 18和pnp。这些发现表明，在新几内亚岛上传播的恶性疟原虫谱系已经逐渐获得了复杂的变体集合，包括kelch 13 C580 Y，这些变体影响了寄生虫的药物敏感性。这一令人担忧的事态发展加强了对岛上不断演变的寄生虫种群进行监测的必要性，以遏制耐药性的传播。青蒿素是治疗恶性疟原虫疟疾最广泛使用的药物。在东南亚，寄生虫已经进化出基因变化，使它们对青蒿素产生抗药性。消除耐药菌株是全球优先事项，因为它们在全球的传播可能导致大量生命损失。在巴布亚新几内亚，我们发现了三名感染寄生虫的患者，他们携带着东南亚最广泛的耐药变异体，他们被证实对青蒿素具有耐药性。我们确定这些突变不是从东南亚进口的，并在其遗传背景中发现了其他耐药性变体，包括一些与印度尼西亚的寄生虫共有的变体。这表明，青蒿素耐药性在新几内亚与东南亚分开出现，不是偶然事件，而是一个渐进的进化过程，可能在岛上仍在进行中未被发现。这些耐药菌株可能会破坏当地的疟疾控制工作，并构成全球威胁。
The rapid and aggressive spread of artemisinin-resistant Plasmodium falciparum carrying the C580Y mutation in the kelch13 gene is a growing threat to malaria elimination in Southeast Asia, but there is no evidence of their spread to other regions. We conducted cross-sectional surveys in 2016 and 2017 at two clinics in Wewak, Papua New Guinea (PNG) where we identified three infections caused by C580Y mutants among 239 genotyped clinical samples. One of these mutants exhibited the highest survival rate (6.8%) among all parasites surveyed in ring-stage survival assays (RSA) for artemisinin. Analyses of kelch13 flanking regions, and comparisons of deep sequencing data from 389 clinical samples from PNG, Indonesian Papua and Western Cambodia, suggested an independent origin of the Wewak C580Y mutation, showing that the mutants possess several distinctive genetic features. Identity by descent (IBD) showed that multiple portions of the mutants’ genomes share a common origin with parasites found in Indonesian Papua, comprising several mutations within genes previously associated with drug resistance, such as mdr1, ferredoxin, atg18 and pnp. These findings suggest that a P. falciparum lineage circulating on the island of New Guinea has gradually acquired a complex ensemble of variants, including kelch13 C580Y, which have affected the parasites’ drug sensitivity. This worrying development reinforces the need for increased surveillance of the evolving parasite populations on the island, to contain the spread of resistance. Artemisinin is the most widely used drug against Plasmodium falciparum malaria. In southeast Asia, parasites have evolved genetic changes making them resistant to artemisinin. The elimination of resistant strains is a global priority, since their global spread could result in massive loss of lives. In Papua New Guinea, we found three patients infected with parasites carrying the most widespread resistant variant in southeast Asia, and they were confirmed to be artemisinin resistant. We established that the mutations were not imported from southeast Asia, and found other drug resistance variants in their genetic background, including some shared with parasites in Indonesia. This indicates that artemisinin resistance has emerged in New Guinea separately from southeast Asia, not by a chance event, but by a gradual process of evolution which may still be ongoing undetected on the island. These resistant strains could undermine malaria local control efforts, and constitute a global threat.
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