Laboratory of Malaria and Vector Research, Office of Cyber Infrastructure and Computational Biology, NIAID, National Institutes of Health, Bethesda, Maryland 20852, USA.
J Biol Chem. 2013 Jul 5;288(27):19429-40. doi: 10.1074/jbc.M113.468371. Epub 2013 May 28.
Acquired antimalarial drug resistance produces treatment failures and has led to periods of global disease resurgence. In Plasmodium falciparum, resistance is known to arise through genome-level changes such as mutations and gene duplications. We now report an epigenetic resistance mechanism involving genes responsible for the plasmodial surface anion channel, a nutrient channel that also transports ions and antimalarial compounds at the host erythrocyte membrane. Two blasticidin S-resistant lines exhibited markedly reduced expression of clag genes linked to channel activity, but had no genome-level changes. Silencing aborted production of the channel protein and was directly responsible for reduced uptake. Silencing affected clag paralogs on two chromosomes and was mediated by specific histone modifications, allowing a rapidly reversible drug resistance phenotype advantageous to the parasite. These findings implicate a novel epigenetic resistance mechanism that involves reduced host cell uptake and is a worrisome liability for water-soluble antimalarial drugs.
获得性抗疟药物耐药性导致治疗失败，并导致全球疾病再次爆发。在恶性疟原虫中，耐药性已知是通过基因组水平的变化如突变和基因重复产生的。我们现在报告一种涉及疟原虫表面阴离子通道相关基因的表观遗传耐药机制，该通道是一种营养通道，也在宿主红细胞膜上运输离子和抗疟化合物。两个博来霉素 S 抗性系表现出与通道活性相关的 clag 基因表达显著降低，但没有基因组水平的变化。沉默导致通道蛋白的产生中止，直接导致摄取减少。沉默影响两条染色体上的 clag 基因，由特定的组蛋白修饰介导，使寄生虫获得快速可逆的耐药表型，这是有利的。这些发现表明涉及宿主细胞摄取减少的新型表观遗传耐药机制，这对抗疟药物是一个令人担忧的缺陷。
