Toxoplasma IWS1 Determines Fitness in Interferon-γ-Activated Host Cells and Mice by Indirectly Regulating ROP18 mRNA Expression.
Toxoplasma IWS1 Determines Fitness in Interferon-γ-Activated Host Cells and Mice by Indirectly Regulating ROP18 mRNA Expression.
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弓形虫可分泌多种毒力效应分子进入宿主细胞，破坏宿主γ-干扰素（IFN-γ）依赖性免疫。在这些效应子中，ROP 18直接磷酸化和失活IFN-诱导型GTP酶，如免疫相关GTP酶（IRGs）和鸟苷酸结合蛋白（GBP），导致IFN-诱导型GTP酶诱导的细胞自主免疫的颠覆。ROP 18的作用模式已被广泛研究;然而，对ROP 18在寄生虫本身中产生的分子机制知之甚少。在这里，我们报告的作用T。弓形虫转录因子IWS 1在疟原虫ROP 18 mRNA表达中的作用。与野生型强毒I型T. IWS 1缺陷型弓形虫的IRG和GBP在寄生虫空泡膜（PVM）上的负载显著增加。此外，IWS 1缺陷型寄生虫在野生型小鼠中表现出毒力下降，但在缺乏IFN-γ受体的小鼠中保持正常毒力。此外，IWS 1缺陷型寄生虫表现出ROP 18 mRNA表达的严重下降;然而，标记的IWS 1不直接与ROP 18基因座的基因组区域结合。在IWS 1缺陷型寄生虫中ROP 18的异位表达恢复了野生型小鼠中PVM和体内毒力的效应子的降低负荷。这些数据表明T.弓形虫IWS 1间接调节ROP 18 mRNA表达，以确定IFN-γ激活的宿主细胞和小鼠中的适应性。
Toxoplasma gondii secretes various virulence effector molecules into host cells to disrupt host interferon-γ (IFN-γ)-dependent immunity. Among these effectors, ROP18 directly phosphorylates and inactivates IFN-inducible GTPases, such as immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs), leading to the subversion of IFN-inducible GTPase-induced cell-autonomous immunity. The modes of action of ROP18 have been studied extensively; however, little is known about the molecular mechanisms by which ROP18 is produced in the parasite itself. Here, we report the role of T. gondii transcription factor IWS1 in ROP18 mRNA expression in the parasite. Compared with wild-type virulent type I T. gondii, IWS1-deficient parasites showed dramatically increased loading of IRGs and GBPs onto the parasitophorous vacuole membrane (PVM). Moreover, IWS1-deficient parasites displayed decreased virulence in wild-type mice but retained normal virulence in mice lacking the IFN-γ receptor. Furthermore, IWS1-deficient parasites showed severely decreased ROP18 mRNA expression; however, tagged IWS1 did not directly bind with genomic regions of the ROP18 locus. Ectopic expression of ROP18 in IWS1-deficient parasites restored the decreased loading of effectors onto the PVM and in vivo virulence in wild-type mice. Taken together, these data demonstrate that T. gondii IWS1 indirectly regulates ROP18 mRNA expression to determine fitness in IFN-γ-activated host cells and mice.
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