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Functional and Computational Genomics Reveal Unprecedented Flexibility in Stage-Specific Toxoplasma Metabolism.
Cell Host & Microbe ( IF 20.6 ) Pub Date : 2020-01-27 , DOI: 10.1016/j.chom.2020.01.002
Aarti Krishnan 1 , Joachim Kloehn 1 , Matteo Lunghi 1 , Anush Chiappino-Pepe 2 , Benjamin S Waldman 3 , Damien Nicolas 1 , Emmanuel Varesio 4 , Adrian Hehl 5 , Sebastian Lourido 6 , Vassily Hatzimanikatis 2 , Dominique Soldati-Favre 1
Affiliation  

To survive and proliferate in diverse host environments with varying nutrient availability, the obligate intracellular parasite Toxoplasma gondii reprograms its metabolism. We have generated and curated a genome-scale metabolic model (iTgo) for the fast-replicating tachyzoite stage, harmonized with experimentally observed phenotypes. To validate the importance of four metabolic pathways predicted by the model, we have performed in-depth in vitro and in vivo phenotyping of mutant parasites including targeted metabolomics and CRISPR-Cas9 fitness screening of all known metabolic genes. This led to unexpected insights into the remarkable flexibility of the parasite, addressing the dependency on biosynthesis or salvage of fatty acids (FAs), purine nucleotides (AMP and GMP), a vitamin (pyridoxal-5P), and a cofactor (heme) in both the acute and latent stages of infection. Taken together, our experimentally validated metabolic network leads to a deeper understanding of the parasite's biology, opening avenues for the development of therapeutic intervention against apicomplexans.

中文翻译:

功能和计算基因组学揭示了特定阶段弓形虫代谢中前所未有的灵活性。

为了在具有不同养分利用率的不同宿主环境中生存和增殖,专性细胞内寄生虫弓形虫会重新编程其代谢。我们已经为快速复制的速殖子阶段生成并策划了一个基因组规模的代谢模型(iTgo),该模型与实验观察到的表型协调一致。为了验证模型预测的四个代谢途径的重要性,我们对突变寄生虫进行了深入的体外和体内表型分析,包括靶向代谢组学和对所有已知代谢基因的CRISPR-Cas9适应性筛选。这导致了对寄生虫非凡灵活性的出乎意料的见解,解决了对脂肪酸(FAs),嘌呤核苷酸(AMP和GMP),维生素(pyridoxal-5P),生物合成或补救的依赖,在急性和潜伏感染阶段都有辅助因子(血红素)。综上所述,我们经过实验验证的代谢网络使人们对寄生虫的生物学有了更深入的了解,为开发抗蚜虫的治疗性干预措施开辟了道路。
更新日期:2020-01-29
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