Plasmodium gene 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 barcoded P. berghei mutants 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 of P. berghei liver-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.

中文翻译：

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针对疟原虫肝阶段的基本代谢过程的基因组规模鉴定。

由于在这些阶段的表型通量的限制，在疟疾和肝脏阶段的疟原虫基因功能仍然很差。为了填补这一空白，我们在整个生命周期中跟踪了1,300多个带条形码的伯氏疟原虫突变体。我们发现有效寄生虫通过肝脏阶段传播到蚊子并回到小鼠血流中所需的461个基因。我们通过建立伯氏疟原虫肝阶段代谢的热力学模型，在基因组，转录组和代谢组学数据的背景下分析屏幕，该模型显示了寄生虫代谢的主要重编程以在肝脏中快速生长。与无性血液阶段相比，我们确定了七个在肝脏阶段必不可少的代谢子系统：II型脂肪酸合成和延伸（FAE），三羧酸，氨基糖，血红素，硫辛酸酯和sh草酸酯代谢。从模型中选择的预测将在单个突变体中单独验证，以为药物开发提供未来的目标。