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Nature:恶性疟原虫疟疾的青蒿素耐药性分子机制

标签:青蒿素 耐药
摘要 : 青蒿素的抗疟疾药物的基础。耐药性的出现和传播的风险提出了清除最近取得的成果在减少全球疟疾负担并威胁未来的疟疾控制和消除在全球水平。

 青蒿素的抗疟疾药物的基础。耐药性的出现和传播的风险提出了清除最近取得的成果在减少全球疟疾负担并威胁未来的疟疾控制和消除在全球水平。全基因组关联研究(GWAS)揭示寄生虫基因位点与青蒿素耐药性有关,此外,以往的恶性疟原虫全基因组关联研究鉴别出了一些与青蒿素耐药有关的近,但却不清楚这些基因的作用机制。这项研究确定了在临床环状体阶段青蒿素的靶点,以及一种叫做的PfKelch13基因(用来追踪疟原虫耐药的一个显性标记)引起青蒿素耐药的机制。

原文链接:

A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria

原文摘要:

Artemisinins are the cornerstone of anti-malarial drugs1. 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 falciparumphosphatidylinositol-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 phosphatidylinositol-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.

来源: Nature 浏览次数:43

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