Artemisinin resistance phenotypes and K13 inheritance in a Plasmodium falciparum cross and Aotus model.
Artemisinin resistance phenotypes and K13 inheritance in a Plasmodium falciparum cross and Aotus model.
复制标题
恶性疟原虫杂交和 Aotus 模型中的青蒿素耐药表型和 K13 遗传。
DOI：
10.1073/pnas.1813386115
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发表时间：
2018
影响因子：
11.1
通讯作者：
Rahman,Rifat
中科院分区：
文献类型：
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作者：
Sá,JulianaM;Kaslow,SarahR;Krause,MichaelA;Melendez-Muniz,VivianaA;Salzman,RebeccaE;Kite,WhitneyA;Zhang,Min;MoraesBarros,RobertoR;Mu,Jianbing;Han,PaulK;Mershon,JPatrick;Figan,ChristineE;Caleon,RamoncitoL;Rahman,Rifat
随着疟原虫清除时间延长t1/2s（> 5小时）及其与恶性疟原虫Kelch-propeller蛋白K13突变的相关性的发现，人们对疟原虫对青蒿素药物（ART）治疗产生耐药性的担忧日益增加。在这里，我们描述aP。 K13 C580Y 突变体与 C580 野生型寄生虫进行恶性疟实验室杂交，以研究体外和体内 ART 反应表型。对超过 400 个分离的后代进行基因分型后，我们在体外评估了 20 个重组体：C580Y 型和 C580 型后代的双氢青蒿素 IC50 测量值处于相似的低纳摩尔水平（平均比率，1.00；95% CI，0.62–1.61），而在环期生存测定中，C580Y 型后代平均计数高 19.6 倍（95% CI，9.76–39.2）。每日三剂静脉注射治疗的脾切除猴。青蒿琥酯，通过三种不同方法计算t1/2，C580Y和C580感染之间的平均差异为0.01小时（95% CI，-3.66至3.67）、0.80小时（95% CI，-0.92至2.53）和2.07小时（95% CI，0.77-3.36）。 C580Y（7 例中的 4 例）感染的复发率为 57%，而 C580（10 例中的 7 例）感染的复发率为 70%（-13% 差异；95% CI，-58% 至 35%）。在含有 C580Y 的后代克隆 (76H10) 中对 C580 进行等位基因取代，产生了转化体 (76H10C580Rev)，在受感染的猴子中，该转化体在 500 天内有规律地复发 13 次。 ART 治疗后频繁复发。无论有或没有 K13 突变，恶性疟原虫感染都会发生，并强调需要改进的配套药物，以有效消除联合治疗的 ART 部分中持续存在的寄生虫。
Concerns about malaria parasite resistance to treatment with artemisinin drugs (ARTs) have grown with findings of prolonged parasite clearancet1/2s (>5 h) and their association with mutations inPlasmodium falciparumKelch-propeller protein K13. Here, we describe aP. falciparumlaboratory cross of K13 C580Y mutant with C580 wild-type parasites to investigate ART response phenotypes in vitro and in vivo. After genotyping >400 isolated progeny, we evaluated 20 recombinants in vitro: IC50measurements of dihydroartemisinin were at similar low nanomolar levels for C580Y- and C580-type progeny (mean ratio, 1.00; 95% CI, 0.62–1.61), whereas, in a ring-stage survival assay, the C580Y-type progeny had 19.6-fold (95% CI, 9.76–39.2) higher average counts. In splenectomizedAotusmonkeys treated with three daily doses of i.v. artesunate,t1/2calculations by three different methods yielded mean differences of 0.01 h (95% CI, −3.66 to 3.67), 0.80 h (95% CI, −0.92 to 2.53), and 2.07 h (95% CI, 0.77–3.36) between C580Y and C580 infections. Incidences of recrudescence were 57% in C580Y (4 of 7) versus 70% in C580 (7 of 10) infections (−13% difference; 95% CI, −58% to 35%). Allelic substitution of C580 in a C580Y-containing progeny clone (76H10) yielded a transformant (76H10C580Rev) that, in an infected monkey, recrudesced regularly 13 times over 500 d. Frequent recrudescences of ART-treatedP. falciparuminfections occur with or without K13 mutations and emphasize the need for improved partner drugs to effectively eliminate the parasites that persist through the ART component of combination therapy.