Artemisinin-resistant K13 mutations rewire Plasmodium falciparum's intra-erythrocytic metabolic program to enhance survival.
Artemisinin-resistant K13 mutations rewire Plasmodium falciparum's intra-erythrocytic metabolic program to enhance survival.
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DOI：
10.1038/s41467-020-20805-w
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发表时间：
2021-01-22
影响因子：
16.6
通讯作者：
Fidock DA
中科院分区：
文献类型：
--
作者：
Mok S;Stokes BH;Gnädig NF;Ross LS;Yeo T;Amaratunga C;Allman E;Solyakov L;Bottrill AR;Tripathi J;Fairhurst RM;Llinás M;Bozdech Z;Tobin AB;Fidock DA
由恶性疟原虫K13突变驱动的青蒿素耐药性的出现和传播损害了抗疟疗效，并威胁到全球消除疟疾运动。通过将基于系统的定量转录组学、蛋白质组学和代谢组学应用于一组等基因K13突变体或野生型恶性疟原虫系，我们提供了K13突变改变寄生虫红细胞内发育程序多个方面的证据。这些变化影响细胞周期的周期性，未折叠的蛋白质反应，蛋白质降解，囊泡运输和线粒体代谢。K13介导的青蒿素抗性在柬埔寨Cam3.II线逆转阿托伐醌，线粒体电子传递链抑制剂。这些结果表明，线粒体过程，包括损伤传感和抗氧化特性可能会增加突变K13的能力，以保护恶性疟原虫对青蒿素的作用，帮助这些寄生虫经历暂时的静止和加速生长恢复后消除药物。青蒿素耐药性的出现和蔓延损害了抗疟疗效。在这里，Mok等人应用定量转录组学、蛋白质组学和代谢组学提供证据，证明K13突变改变了寄生虫红细胞内发育的多个方面，以提高青蒿素治疗后的存活率。
The emergence and spread of artemisinin resistance, driven by mutations in Plasmodium falciparum K13, has compromised antimalarial efficacy and threatens the global malaria elimination campaign. By applying systems-based quantitative transcriptomics, proteomics, and metabolomics to a panel of isogenic K13 mutant or wild-type P. falciparum lines, we provide evidence that K13 mutations alter multiple aspects of the parasite’s intra-erythrocytic developmental program. These changes impact cell-cycle periodicity, the unfolded protein response, protein degradation, vesicular trafficking, and mitochondrial metabolism. K13-mediated artemisinin resistance in the Cambodian Cam3.II line was reversed by atovaquone, a mitochondrial electron transport chain inhibitor. These results suggest that mitochondrial processes including damage sensing and anti-oxidant properties might augment the ability of mutant K13 to protect P. falciparum against artemisinin action by helping these parasites undergo temporary quiescence and accelerated growth recovery post drug elimination. The emergence and spread of artemisinin resistance has compromised antimalarial efficacy. Here, Mok et al. apply quantitative transcriptomics, proteomics, and metabolomics to provide evidence that K13 mutations alter multiple aspects of the parasite’s intra-erythrocytic development to enhance survival following artemisinin treatment.
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柬埔寨恶性疟原虫疟疾中的双氢青蒿素-哌喹抗药性：一项多地点前瞻性队列研究。
DOI：
10.1016/s1473-3099(15)00487-9
发表时间：
2016-03
期刊：
The Lancet. Infectious diseases
影响因子：
--
作者：
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影响因子：
6.7
作者：
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通讯作者：
Fidock, David A.
影响因子：
46.9
作者：
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影响因子：
16.6
作者：
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Tobin AB
影响因子：
12.3
作者：
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通讯作者：
Neafsey DE