Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage
Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage
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DOI：
10.1016/j.cell.2019.10.030
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发表时间：
2019-11-14
期刊：
影响因子：
64.5
通讯作者：
Heussler，Volker T.
中科院分区：
文献类型：
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作者：
Stanway，Rebecca R.;Bushell，Ellen;Heussler，Volker T.
疟原虫基因在蚊子和肝脏阶段的功能仍然很差的特点，由于在这些阶段的表型的吞吐量的限制。为了填补这一空白，我们跟踪了1,300多个条形码伯氏疟原虫的生命周期。我们发现了461个基因，这些基因是寄生虫通过肝脏阶段有效传播到蚊子并返回到小鼠血液中所必需的。我们通过构建伯氏疟原虫肝脏阶段代谢的热力学模型，在基因组学、转录组学和代谢组学数据的背景下分析了筛选，该模型显示了寄生虫代谢的主要重编程以实现肝脏中的快速生长。我们确定了7个代谢子系统，成为必不可少的肝脏阶段相比，无性血液阶段：II型脂肪酸的合成和延伸（FAE），三羧酸，氨基糖，血红素，硫辛酸和莽草酸代谢。从模型中选择的预测在单个突变体中单独验证，为药物开发提供未来的目标。
Plasmodiumgene functions in mosquito and liver stages remain poorly characterized due to limitations in the throughput of phenotyping at these stages. To fill this gap, we followed more than 1,300 barcodedP. bergheimutants through the life cycle. We discover 461 genes required for efficient parasite transmission to mosquitoes through the liver stage and back into the bloodstream of mice. We analyze the screen in the context of genomic, transcriptomic, and metabolomic data by building a thermodynamic model ofP. bergheiliver-stage metabolism, which shows a major reprogramming of parasite metabolism to achieve rapid growth in the liver. We identify seven metabolic subsystems that become essential at the liver stages compared with asexual blood stages: type II fatty acid synthesis and elongation (FAE), tricarboxylic acid, amino sugar, heme, lipoate, and shikimate metabolism. Selected predictions from the model are individually validated in single mutants to provide future targets for drug development.