Proteomic Profiling of Mouse Liver following Acute Toxoplasma gondii Infection

Toxoplasma gondii remains a global public health problem. However, its pathophysiology is still not-completely understood particularly the impact of infection on host liver metabolism. We performed iTRAQ-based proteomic analysis to evaluate early liver protein responses in BALB/c mice following infection with T. gondii PYS strain (genotype ToxoDB#9) infection. Our data revealed modification of protein expression in key metabolic pathways, as indicated by the upregulation of immune response and downregulation of mitochondrial respiratory chain, and the metabolism of fatty acids, lipids and xenobiotics. T. gondii seems to hijack host PPAR signaling pathway to downregulate the metabolism of fatty acids, lipids and energy in the liver. The metabolism of over 400 substances was affected by the downregulation of genes involved in xenobiotic metabolism. The top 10 transcription factors used by upregulated genes were Stat2, Stat1, Irf2, Irf1, Sp2, Egr1, Stat3, Klf4, Elf1 and Gabpa, while the top 10 transcription factors of downregulated genes were Hnf4A, Ewsr1, Fli1, Hnf4g, Nr2f1, Pparg, Rxra, Hnf1A, Foxa1 and Foxo1. These findings indicate global reprogramming of the metabolism of the mouse liver after acute T. gondii infection. Functional characterization of the altered proteins may enhance understanding of the host responses to T. gondii infection and lead to the identification of new therapeutic targets.刚地弓形虫（Toxoplasma gondii）仍是全球性公共卫生难题。然而，其致病机制至今尚未完全阐明，尤其是感染对宿主肝脏代谢的影响仍有待深入解析。本研究采用基于iTRAQ的蛋白质组学分析方法，评估了BALB/c小鼠感染刚地弓形虫PYS株（基因型为ToxoDB#9）后的早期肝脏蛋白质应答反应。研究数据显示，关键代谢通路的蛋白表达谱发生显著改变：免疫应答相关蛋白表达上调，而线粒体呼吸链功能、脂肪酸、脂质及外源性物质代谢相关蛋白则出现下调。刚地弓形虫似乎通过劫持宿主过氧化物酶体增殖物激活受体（PPAR）信号通路，下调肝脏内脂肪酸、脂质及能量代谢过程。超过400种物质的代谢过程因外源性物质代谢相关基因的表达下调而受到影响。上调基因所富集的前10种转录因子依次为Stat2、Stat1、Irf2、Irf1、Sp2、Egr1、Stat3、Klf4、Elf1及Gabpa；而下调基因所富集的前10种转录因子则为Hnf4A、Ewsr1、Fli1、Hnf4g、Nr2f1、Pparg、Rxra、Hnf1A、Foxa1及Foxo1。上述研究结果表明，急性刚地弓形虫感染后，小鼠肝脏代谢发生了全局性重编程。对这些差异表达蛋白进行功能表征，有助于加深宿主抗弓形虫感染应答机制的认知，并有望发掘新型治疗靶点。