瑞士伯尔尼大学Volker T. Heussler和英国惠康桑格研究所Oliver Billker团队合作，针对疟原虫肝阶段的基本代谢过程进行基因组规模的鉴定。该研究2019年11月14日发表于国际学术期刊《细胞》。
为了填补疟疾和肝脏阶段的疟原虫基因功能的空白，研究人员在整个生命周期中追踪了1,300个带条形码的伯氏疟原虫突变体。他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液中所需的461个基因。研究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筛选，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，他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、硫辛酸酯和莽草酸酯代谢。从模型中选择的预测将在单个突变体中单独验证，以为药物开发提供有望靶标。
研究人员表示，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未被鉴定。
附：英文原文
Title: Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage
Author: Rebecca R. Stanway, Ellen Bushell, Anush Chiappino-Pepe, Magali Roques, Theo Sanderson, Blandine Franke-Fayard, Reto Caldelari, Murielle Golomingi, Mary Nyonda, Vikash Pandey, Frank Schwach, Séverine Chevalley, Jai Ramesar, Tom Metcalf, Colin Herd, Paul-Christian Burda, Julian C. Rayner, Dominique Soldati-Favre, Chris J. Janse, Vassily Hatzimanikatis, Oliver Billker, Volker T. Heussler
Issue&Volume: 2019/11/14
Abstract: 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.
DOI: 10.1016/j.cell.2019.10.030
Source: https://www.cell.com/cell/fulltext/S0092-8674(19)31180-8