Natalang Onguma, Bischoff Emmanuel, Deplaine Guillaume, Proux Caroline, Dillies Marie-Agnès, Sismeiro Odile, Guigon Ghislaine, Bonnefoy Serge, Patarapotikul Jintana, Mercereau-Puijalon Odile, Coppée Jean-Yves, David Peter H
Institut Pasteur, Unité d'Immunologie Moléculaire des Parasites, CNRS URA 2581, 28 Rue du Docteur Roux, F-75724, Paris, Cedex 15, France.
BMC Genomics. 2008 Aug 18;9:388. doi: 10.1186/1471-2164-9-388.
Translation of the genome sequence of Plasmodium sp. into biologically relevant information relies on high through-put genomics technology which includes transcriptome analysis. However, few studies to date have used this powerful approach to explore transcriptome alterations of P. falciparum parasites exposed to antimalarial drugs.
The rapid action of artesunate allowed us to study dynamic changes of the parasite transcriptome in synchronous parasite cultures exposed to the drug for 90 minutes and 3 hours. Developmentally regulated genes were filtered out, leaving 398 genes which presented altered transcript levels reflecting drug-exposure. Few genes related to metabolic pathways, most encoded chaperones, transporters, kinases, Zn-finger proteins, transcription activating proteins, proteins involved in proteasome degradation, in oxidative stress and in cell cycle regulation. A positive bias was observed for over-expressed genes presenting a subtelomeric location, allelic polymorphism and encoding proteins with potential export sequences, which often belonged to subtelomeric multi-gene families. This pointed to the mobilization of processes shaping the interface between the parasite and its environment. In parallel, pathways were engaged which could lead to parasite death, such as interference with purine/pyrimidine metabolism, the mitochondrial electron transport chain, proteasome-dependent protein degradation or the integrity of the food vacuole.
The high proportion of over-expressed genes encoding proteins exported from the parasite highlight the importance of extra-parasitic compartments as fields for exploration in drug research which, to date, has mostly focused on the parasite itself rather than on its intra and extra erythrocytic environment. Further work is needed to clarify which transcriptome alterations observed reflect a specific response to overcome artesunate toxicity or more general perturbations on the path to cellular death.
疟原虫属的基因组序列转化为生物学相关信息依赖于高通量基因组学技术，其中包括转录组分析。然而，迄今为止，很少有研究使用这种强大的方法来探索暴露于抗疟药物的恶性疟原虫转录组的变化。
青蒿琥酯的快速作用使我们能够研究同步寄生虫培养物中寄生虫转录组在暴露于该药物90分钟和3小时后的动态变化。去除发育调控基因后，剩下398个基因的转录水平发生改变，反映了药物暴露情况。与代谢途径相关的基因很少，大多数编码伴侣蛋白、转运蛋白、激酶、锌指蛋白、转录激活蛋白、参与蛋白酶体降解、氧化应激和细胞周期调控的蛋白。观察到过表达基因存在正偏差，这些基因位于亚端粒位置、具有等位基因多态性且编码具有潜在输出序列的蛋白，这些蛋白通常属于亚端粒多基因家族。这表明塑造寄生虫与其环境之间界面的过程被激活。同时，一些途径被激活，可能导致寄生虫死亡，例如干扰嘌呤/嘧啶代谢、线粒体电子传递链、蛋白酶体依赖性蛋白降解或食物泡的完整性。
编码从寄生虫输出的蛋白的过表达基因比例很高，这突出了寄生细胞外区室作为药物研究探索领域的重要性，迄今为止，药物研究大多集中在寄生虫本身，而非其红细胞内和红细胞外环境。需要进一步开展工作，以阐明观察到的哪些转录组变化反映了克服青蒿琥酯毒性的特定反应，或细胞死亡途径上更普遍的扰动。
