Genome-wide compensatory changes accompany drug- selected mutations in the Plasmodium falciparum crt gene.
Genome-wide compensatory changes accompany drug- selected mutations in the Plasmodium falciparum crt gene.
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DOI：
10.1371/journal.pone.0002484
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发表时间：
2008-06-25
期刊：
影响因子：
3.7
通讯作者：
Su XZ
中科院分区：
文献类型：
--
作者：
Jiang H;Patel JJ;Yi M;Mu J;Ding J;Stephens R;Cooper RA;Ferdig MT;Su XZ
PfCRT（恶性疟原虫氯喹抗性转运蛋白）中的突变，特别是氨基酸位置76处的取代，赋予恶性疟原虫氯喹（CQ）抗性。哺乳动物多药耐药基因（pfmdr 1）同源物的点突变也可以调节CQ反应水平。此外，具有相同pfcrt和pfmdr 1等位基因的寄生虫表现出广泛的药物敏感性，这表明其他基因有助于CQ抗性（CQR）水平。CQ敏感性寄生虫在停止使用CQ后重新出现，表明PfCRT的变化对寄生虫有害。然而，一些CQR寄生虫在田间持续存在并在培养物中生长良好，这可能反映了寄生虫基因组的适应性变化，以补偿PfCRT中的突变。使用三个同基因克隆，具有不同的耐药谱对应于独特的突变pfcrt基因（106/1 K76，106/176 I，和106/76 I-352 K），我们研究了基因表达的变化，这些寄生虫生长与CQ和没有。我们还进行了基因组DNA杂交，以确定寄生虫基因的拷贝数（CN）变化。相对于亲本系106/1 K76，45个基因的RNA转录水平在一个或两个突变体中显著改变。大多数上调的基因参与侵袭、细胞生长和发育、信号转导和运输活动。特别感兴趣的是编码参与细胞质或隔室pH的转运和/或调节的蛋白质的基因，例如V型H+泵焦磷酸酶2（PfVP 2）、Ca 2 +/H+反向转运蛋白VCX 1（pfmdr 1中的推定药物转运蛋白和CN变化）。这些变化可能代表了对PfCRT功能改变的适应，PfCRT是寄生虫食物泡（FV）膜上发现的药物/代谢物转运蛋白超家族的预测成员。对这些基因的进一步研究可能有助于了解寄生虫如何补偿膜/药物转运蛋白基因编码中伴随耐药突变的功能变化。
Mutations in PfCRT (Plasmodium falciparum chloroquine-resistant transporter), particularly the substitution at amino acid position 76, confer chloroquine (CQ) resistance in P. falciparum. Point mutations in the homolog of the mammalian multidrug resistance gene (pfmdr1) can also modulate the levels of CQ response. Moreover, parasites with the same pfcrt and pfmdr1 alleles exhibit a wide range of drug sensitivity, suggesting that additional genes contribute to levels of CQ resistance (CQR). Reemergence of CQ sensitive parasites after cessation of CQ use indicates that changes in PfCRT are deleterious to the parasite. Some CQR parasites, however, persist in the field and grow well in culture, which may reflect adaptive changes in the parasite genome to compensate for the mutations in PfCRT. Using three isogenic clones that have different drug resistance profiles corresponding to unique mutations in the pfcrt gene (106/1K76, 106/176I, and 106/76I-352K), we investigated changes in gene expression in these parasites grown with and without CQ. We also conducted hybridizations of genomic DNA to identify copy number (CN) changes in parasite genes. RNA transcript levels from 45 genes were significantly altered in one or both mutants relative to the parent line, 106/1K76. Most of the up-regulated genes are involved in invasion, cell growth and development, signal transduction, and transport activities. Of particular interest are genes encoding proteins involved in transport and/or regulation of cytoplasmic or compartmental pH such as the V-type H+ pumping pyrophosphatase 2 (PfVP2), Ca2+/H+ antiporter VCX1, a putative drug transporter and CN changes in pfmdr1. These changes may represent adaptations to altered functionality of PfCRT, a predicted member of drug/metabolite transporter superfamily found on the parasite food vacuole (FV) membrane. Further investigation of these genes may shed light on how the parasite compensates for functional changes accompanying drug resistance mutations in a gene coding for a membrane/drug transporter.
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影响因子：
9.8
作者：
Bozdech, Zbynek;Llinas, Manuel;Pulliam, Brian Lee;Wong, Edith D;Zhu, Jingchun;DeRisi, Joseph L
通讯作者：
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DOI：
10.1073/pnas.91.3.1143
发表时间：
1994-02-01
影响因子：
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