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A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria

机译：恶性疟原虫疟疾中青蒿素耐药的分子机制

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摘要

Artemisinins are the cornerstone of anti-malarial drugs'. Emergence and spread of resistance to them' raises risk of wiping out recent gains achieved in reducing worldwide malaria burden and threatens future malaria control and elimination on a global level. Genome-wide association studies (GWAS) have revealed parasite genetic loci associated with artemisinin resistance'''. However, there is no consensus on biochemical targets of artemisinin. Whether and how these targets interact with genes identified by GWAS, remains unknown. Here we provide biochemical and cellular evidence that artemisinins are potent inhibitors of Plasmodium falciparum phosphatidylinosito1-3-kinase (PfPI3K), revealing an unexpected mechanism of action. In resistant clinical strains, increased PfPI3K was associated with the C580Y mutation in P. falciparum Kelch13 (PfKelch13), a primary marker of artemisinin resistance. Polyubiquitination of PfPI3K and its binding to PfKelch13 were reduced by the PfKelch13 mutation, which limited proteolysis of PfPI3K and thus increased levels of the kinase, as well as its lipid product phosphatidylinosito1-3-phosphate (PI3P). We find PI3P levels to be predictive of artemisinin resistance in both clinical and engineered laboratory parasites as well as across non-isogenic strains. Elevated PI3P induced artemisinin resistance in absence of PfKelch13 mutations, but remained responsive to regulation by PfKelch13. Evidence is presented for PI3P-dependent signalling in which transgenic expression of an additional kinase confers resistance. Together these data present PI3P as the key mediator of artemisinin resistance and the sole PfPI3K as an important target for malaria elimination.
机译：青蒿素是抗疟疾药物的基石。对它们的抵抗力的出现和蔓延增加了抹去近期在减轻全球疟疾负担方面取得的成就的风险，并威胁到未来在全球范围内对疟疾的控制和消除。全基因组关联研究（GWAS）已发现与青蒿素抗性有关的寄生虫遗传基因座''。但是，关于青蒿素的生化靶标尚无共识。这些靶标是否与GWAS鉴定的基因相互作用以及如何相互作用尚不清楚。在这里，我们提供了生化和细胞证据，表明青蒿素是恶性疟原虫磷脂酰肌醇1-3激酶（PfPI3K）的有效抑制剂，揭示了意想不到的作用机制。在耐药的临床菌株中，PfPI3K的增加与青蒿素耐药性的主要标志恶性疟原虫Kelch13（PfKelch13）中的C580Y突变有关。 PfKelch13突变减少了PfPI3K的多聚泛素化及其与PfKelch13的结合，这限制了PfPI3K的蛋白水解作用，从而增加了激酶的水平，以及其脂质产物磷脂酰肌醇1-3-磷酸（PI3P）。我们发现PI3P水平可预测临床和工程实验室寄生虫以及非同基因菌株中的青蒿素耐药性。在没有PfKelch13突变的情况下，PI3P诱导的青蒿素耐药性升高，但仍对PfKelch13的调节反应。提供了PI3P依赖性信号传导的证据，其中另外的激酶的转基因表达赋予了抗性。这些数据共同表明，PI3P是青蒿素耐药性的关键介体，而唯一的PfPI3K是消除疟疾的重要目标。

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  • 来源
    《Nature》 |2015年第7549期|683-687|共5页
  • 作者

    Mbengue Alassane; Bhattacharjee Souvik; Pandharkar Trupti; Liu Haining; Estiu Guillermina; Stahelin Robert V.; Rizk Shahir S.; Njimoh Dieudonne L.; Ryan Yana; Chotivanich Kesinee; Nguon Chea; Ghorbal Mehdi; Lopez-Rubio Jose-Juan; Pfrender Michael; Emrich Scott; Mohandas Narla; Dondorp Arjen M.; Wiest Olaf; Haldar Kasturi;

  • 作者单位

    Univ Notre Dame, Boler Parseghian Ctr Rare & Neglected Dis, Notre Dame, IN 46556 USA|Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA;

    Univ Notre Dame, Boler Parseghian Ctr Rare & Neglected Dis, Notre Dame, IN 46556 USA|Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA;

    Univ Notre Dame, Boler Parseghian Ctr Rare & Neglected Dis, Notre Dame, IN 46556 USA|Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA;

    Univ Notre Dame, Boler Parseghian Ctr Rare & Neglected Dis, Notre Dame, IN 46556 USA|Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA;

    Univ Notre Dame, Boler Parseghian Ctr Rare & Neglected Dis, Notre Dame, IN 46556 USA|Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA;

    Univ Notre Dame, Boler Parseghian Ctr Rare & Neglected Dis, Notre Dame, IN 46556 USA|Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA|Indiana Univ Sch Med, Dept Biochem & Mol Biol, South Bend, IN 46617 USA;

    Univ Notre Dame, Boler Parseghian Ctr Rare & Neglected Dis, Notre Dame, IN 46556 USA|Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA;

    Univ Notre Dame, Boler Parseghian Ctr Rare & Neglected Dis, Notre Dame, IN 46556 USA|Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA|Univ Buea, Fac Sci, Dept Biochem & Mol Biol, Buea, Southwest Regio, Cameroon;

    Univ Notre Dame, Boler Parseghian Ctr Rare & Neglected Dis, Notre Dame, IN 46556 USA|Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA;

    Mahidol Univ, Fac Trop Med, Bangkok 10400, Thailand;

    Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh 12302, Cambodia;

    Univ Montpellier 1&2 MiVEGEC, CNRS 5290, IRD 224, Montpellier, France;

    Univ Montpellier 1&2 MiVEGEC, CNRS 5290, IRD 224, Montpellier, France;

    Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA;

    Univ Notre Dame, Dept Comp Sci & Engn, Notre Dame, IN 46556 USA;

    New York Blood Ctr, New York, NY 10032 USA;

    Mahidol Univ, Fac Trop Med, Bangkok 10400, Thailand|Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford OX3 7BN, England;

    Univ Notre Dame, Boler Parseghian Ctr Rare & Neglected Dis, Notre Dame, IN 46556 USA|Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA|Peking Univ, Shenzhen Grad Sch, Lab Chem Genom, Lab Computat Chem & Drug Design, Shenzhen 518055, Peoples R China;

    Univ Notre Dame, Boler Parseghian Ctr Rare & Neglected Dis, Notre Dame, IN 46556 USA|Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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