Artemisinin resistance in rodent malaria - mutation in the AP2 adaptor μ-chain suggests involvement of endocytosis and membrane protein trafficking
Artemisinin resistance in rodent malaria - mutation in the AP2 adaptor μ-chain suggests involvement of endocytosis and membrane protein trafficking
复制标题
DOI：
10.1186/1475-2875-12-118
复制
发表时间：
2013-04-05
期刊：
影响因子：
3
通讯作者：
Cravo, Pedro
中科院分区：
文献类型：
--
作者：
Henriques, Gisela;Martinelli, Axel;Cravo, Pedro
背景：恶性疟原虫（Plasmodium falciparum）引起的疟疾的控制受到耐药性不断演变的阻碍。由于青蒿素衍生物目前用于最有效的抗疟疾治疗，对青蒿素的耐药性将是灾难性的。事实上，研究表明，自然感染中已经出现了对青蒿素的耐药性。了解耐药机制将有助于延长这些药物的有效寿命。因此，迫切需要抗性的遗传标记。此前，一种去泛素化酶的突变被证明会使啮齿动物疟疾寄生虫沙巴蒂疟原虫产生青蒿素耐药性。方法：利用Illumina全基因组重测序技术，对突变型夏波疟原虫及其直系祖疟原虫的体内青蒿素耐药表型和突变进行比较。结果：增加的青蒿素耐药表型伴随着一个非同义替代。突变基因编码AP2接头复合体的mu链，AP2接头复合体是内吞机制的一个组成部分。同源性模型表明突变残基与货物识别序列相互作用。在自然感染的人疟原虫恶性疟原虫中，在同源基因中鉴定出12个多态性（9个snp和3个indel）。结论：增加的青蒿素耐药表型与AP2接头蛋白复合物功能元件的突变一起发生。这表明内吞作用和膜蛋白的运输可能参与其中，为可能的耐药机制提供了新的见解。该接头蛋白的基因型可用于评估其在人恶性疟原虫感染中青蒿素反应中的作用。
Background: The control of malaria, caused by Plasmodium falciparum, is hampered by the relentless evolution of drug resistance. Because artemisinin derivatives are now used in the most effective anti-malarial therapy, resistance to artemisinin would be catastrophic. Indeed, studies suggest that artemisinin resistance has already appeared in natural infections. Understanding the mechanisms of resistance would help to prolong the effective lifetime of these drugs. Genetic markers of resistance are therefore required urgently. Previously, a mutation in a de-ubiquitinating enzyme was shown to confer artemisinin resistance in the rodent malaria parasite Plasmodium chabaudi.Methods: Here, for a mutant P. chabaudi malaria parasite and its immediate progenitor, the in vivo artemisinin resistance phenotypes and the mutations arising using Illumina whole-genome re-sequencing were compared.Results: An increased artemisinin resistance phenotype is accompanied by one non-synonymous substitution. The mutated gene encodes the mu-chain of the AP2 adaptor complex, a component of the endocytic machinery. Homology models indicate that the mutated residue interacts with a cargo recognition sequence. In natural infections of the human malaria parasite P. falciparum, 12 polymorphisms (nine SNPs and three indels) were identified in the orthologous gene.Conclusion: An increased artemisinin-resistant phenotype occurs along with a mutation in a functional element of the AP2 adaptor protein complex. This suggests that endocytosis and trafficking of membrane proteins may be involved, generating new insights into possible mechanisms of resistance. The genotypes of this adaptor protein can be evaluated for its role in artemisinin responses in human infections of P. falciparum.