The Mu subunit of Plasmodium falciparum clathrin-associated adaptor protein 2 modulates in vitro parasite response to artemisinin and quinine.
The Mu subunit of Plasmodium falciparum clathrin-associated adaptor protein 2 modulates in vitro parasite response to artemisinin and quinine.
复制标题
恶性疟原虫网状蛋白相关的衔接蛋白2的MU亚基在体外寄生虫对青蒿素和奎宁的反应调节。
DOI：
10.1128/aac.04067-14
复制
发表时间：
2015-05
影响因子：
4.9
通讯作者：
Sutherland CJ
中科院分区：
文献类型：
--
作者：
Henriques G;van Schalkwyk DA;Burrow R;Warhurst DC;Thompson E;Baker DA;Fidock DA;Hallett R;Flueck C;Sutherland CJ
抗药性寄生虫的出现是疟疾控制计划面临的严重威胁。了解耐药性的遗传基础对于治疗和干预战略的成功至关重要。最近在对啮齿类疟原虫夏氏疟原虫（Pcap 2-mu）的研究中发现了一个与抗疟药耐药性相关的新基因座ap 2-mu（编码衔接蛋白2 [AP 2]复合物的mu链）。此外，在肯尼亚疟疾患者中对恶性疟原虫ap 2-mu同源物pfap 2-mu的多态性进行的分析发现，密码子160编码的氨基酸的差异与包括青蒿素衍生物在内的联合治疗后体内寄生虫存活率的提高有关。在这里，我们的特点是pfap 2-mu在介导恶性疟原虫的体外抗疟药物反应的作用，通过产生组成型表达密码子160编码野生型Ser（Ser 160）或Asn突变体（160 Asn）形式的pfap 2-mu的转基因寄生虫。携带pfap 2-mu 160 Asn等位基因的转基因寄生虫使用标准48小时体外试验对双氢青蒿素的敏感性显着降低，提供了寄生虫对青蒿素反应改变的直接证据。我们的数据也提供了证据表明pfap 2-mu变异体可以调节寄生虫对奎宁的敏感性。没有证据表明pfap 2-mu变异体有助于青蒿琥酯单药治疗的柬埔寨患者中恶性疟原虫表现出的缓慢清除表型。这些发现提供了令人信服的证据，pfap 2-mu可以调节恶性疟原虫对多种药物的反应。我们建议，该基因应进一步评估作为一个潜在的抗疟药耐药的分子标记。
The emergence of drug-resistant parasites is a serious threat faced by malaria control programs. Understanding the genetic basis of resistance is critical to the success of treatment and intervention strategies. A novel locus associated with antimalarial resistance, ap2-mu (encoding the mu chain of the adaptor protein 2 [AP2] complex), was recently identified in studies on the rodent malaria parasite Plasmodium chabaudi (pcap2-mu). Furthermore, analysis in Kenyan malaria patients of polymorphisms in the Plasmodium falciparum ap2-mu homologue, pfap2-mu, found evidence that differences in the amino acid encoded by codon 160 are associated with enhanced parasite survival in vivo following combination treatments which included artemisinin derivatives. Here, we characterize the role of pfap2-mu in mediating the in vitro antimalarial drug response of P. falciparum by generating transgenic parasites constitutively expressing codon 160 encoding either the wild-type Ser (Ser160) or the Asn mutant (160Asn) form of pfap2-mu. Transgenic parasites carrying the pfap2-mu 160Asn allele were significantly less sensitive to dihydroartemisinin using a standard 48-h in vitro test, providing direct evidence of an altered parasite response to artemisinin. Our data also provide evidence that pfap2-mu variants can modulate parasite sensitivity to quinine. No evidence was found that pfap2-mu variants contribute to the slow-clearance phenotype exhibited by P. falciparum in Cambodian patients treated with artesunate monotherapy. These findings provide compelling evidence that pfap2-mu can modulate P. falciparum responses to multiple drugs. We propose that this gene should be evaluated further as a potential molecular marker of antimalarial resistance.