Genome-wide transcriptome profiling reveals functional networks involving the Plasmodium falciparum drug resistance transporters PfCRT and PfMDR1.
Genome-wide transcriptome profiling reveals functional networks involving the Plasmodium falciparum drug resistance transporters PfCRT and PfMDR1.
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DOI：
10.1186/s12864-015-2320-8
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发表时间：
2015-12-21
期刊：
影响因子：
4.4
通讯作者：
Fidock DA
中科院分区：
文献类型：
--
作者：
Adjalley SH;Scanfeld D;Kozlowski E;Llinás M;Fidock DA
恶性疟原虫获得多药耐药性突出表明，需要了解潜在的分子机制，以抵消其对疟疾控制的影响。对于许多抗疟药，其作用方式与抑制感染红细胞内的血红素解毒有关，消化泡转运蛋白PfCRT和PfMDR 1构成了主要的耐药决定因素。我们使用寄生虫红细胞内发育周期过程中的基因表达微阵列，比较了显示突变型或野生型pfcrt或pfcrt或pfmdr 1表达水平不同的恶性疟原虫菌株之间的转录组谱。为了解释采样时间的差异，我们开发了一种称为时间序列超几何分析的计算方法，该方法将快速傅立叶变换与修改后的基因集富集分析相结合。我们的分析揭示了参与蛋白质催化、翻译起始和DNA/RNA代谢的基因的协调变化。我们还观察到差异表达的基因在运输或编码的消化泡的组成部分的作用。有趣的是，对所有转录组进行的全球比较发现，pfcrt和pfmdr 1的转录水平之间存在紧密的相关性，并延伸到数十个其他基因，这表明为了维持最佳生理过程，存在复杂的调节平衡。这项研究提供了深入了解的机制，恶性疟原虫调整收购的突变或基因扩增的关键转运基因座介导的耐药性。我们的研究结果涉及几个生物学途径，可能是差异调节，以弥补受损的转运功能和寄生虫液泡生理学的改变。本文的在线版本（doi：10.1186/s12864-015-2320-8）包含补充材料，可供授权用户使用。
The acquisition of multidrug resistance by Plasmodium falciparum underscores the need to understand the underlying molecular mechanisms so as to counter their impact on malaria control. For the many antimalarials whose mode of action relates to inhibition of heme detoxification inside infected erythrocytes, the digestive vacuole transporters PfCRT and PfMDR1 constitute primary resistance determinants. Using gene expression microarrays over the course of the parasite intra-erythrocytic developmental cycle, we compared the transcriptomic profiles between P. falciparum strains displaying mutant or wild-type pfcrt or varying in pfcrt or pfmdr1 expression levels. To account for differences in the time of sampling, we developed a computational method termed Hypergeometric Analysis of Time Series, which combines Fast Fourier Transform with a modified Gene Set Enrichment Analysis. Our analysis revealed coordinated changes in genes involved in protein catabolism, translation initiation and DNA/RNA metabolism. We also observed differential expression of genes with a role in transport or coding for components of the digestive vacuole. Interestingly, a global comparison of all profiled transcriptomes uncovered a tight correlation between the transcript levels of pfcrt and pfmdr1, extending to dozens of other genes, suggesting an intricate regulatory balance in order to maintain optimal physiological processes. This study provides insight into the mechanisms by which P. falciparum adjusts to the acquisition of mutations or gene amplification in key transporter loci that mediate drug resistance. Our results implicate several biological pathways that may be differentially regulated to compensate for impaired transporter function and alterations in parasite vacuole physiology. The online version of this article (doi:10.1186/s12864-015-2320-8) contains supplementary material, which is available to authorized users.