A genomic and evolutionary approach reveals non-genetic drug resistance in malaria
A genomic and evolutionary approach reveals non-genetic drug resistance in malaria
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DOI：
10.1186/s13059-014-0511-2
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发表时间：
2014-01-01
期刊：
影响因子：
12.3
通讯作者：
Wirth, Dyann F.
中科院分区：
文献类型：
--
作者：
Herman, Jonathan D.;Rice, Daniel P.;Wirth, Dyann F.
背景：耐药性仍然是疟疾治疗和根除的一个主要公共卫生挑战。与许多抗疟药物的耐药性相关的个别位点已被确定，但他们的上位性与其他耐药机制尚未elaborated.Results：我们以前描述了两个突变的细胞质脯氨酰-tRNA合成酶（cPRS）基因，赋予抗药性常山酮。我们在这里描述的两个独立的抗药性选择在恶性疟原虫的常山酮耐药性的演变轨迹。使用这种新的方法，我们发现了恶性疟原虫在对cPRS进行遗传修饰之前利用的一种意想不到的非遗传耐药机制。恶性疟原虫首先上调其脯氨酸氨基酸稳态响应于常山酮压力。我们表明，这种非遗传适应halofuginone是不可能介导的差异RNA表达和cPRS基因的突变或扩增之前。通过全基因组测序跟踪两种耐药选择的进化，我们进一步证明了cPRS基因座占恶性疟原虫对常山酮遗传适应的大部分。我们进一步验证，拷贝数的变化在cPRS基因座也有助于常山酮resistance.Conclusions：我们提供了一个三步模型的多位点进化的常山酮耐药恶性疟原虫。通过基因组方法，我们的研究结果提供了疟疾寄生虫实现耐药性的进化轨迹的第一个全面视图。我们对耐药性的多种遗传和非遗传机制的理解，为我们如何设计和配对未来的抗疟疾药物用于临床提供了信息。
Background: Drug resistance remains a major public health challenge for malaria treatment and eradication. Individual loci associated with drug resistance to many antimalarials have been identified, but their epistasis with other resistance mechanisms has not yet been elucidated.Results: We previously described two mutations in the cytoplasmic prolyl-tRNA synthetase (cPRS) gene that confer resistance to halofuginone. We describe here the evolutionary trajectory of halofuginone resistance of two independent drug resistance selections in Plasmodium falciparum. Using this novel methodology, we discover an unexpected non-genetic drug resistance mechanism that P. falciparum utilizes before genetic modification of the cPRS. P. falciparum first upregulates its proline amino acid homeostasis in response to halofuginone pressure. We show that this non-genetic adaptation to halofuginone is not likely mediated by differential RNA expression and precedes mutation or amplification of the cPRS gene. By tracking the evolution of the two drug resistance selections with whole genome sequencing, we further demonstrate that the cPRS locus accounts for the majority of genetic adaptation to halofuginone in P. falciparum. We further validate that copy-number variations at the cPRS locus also contribute to halofuginone resistance.Conclusions: We provide a three-step model for multi-locus evolution of halofuginone drug resistance in P. falciparum. Informed by genomic approaches, our results provide the first comprehensive view of the evolutionary trajectory malaria parasites take to achieve drug resistance. Our understanding of the multiple genetic and non-genetic mechanisms of drug resistance informs how we will design and pair future anti-malarials for clinical use.