Toxoplasma gondii dysregulates IFN-γ-inducible gene expression in human fibroblasts:: Insights from a genome-wide transcriptional profiling
Toxoplasma gondii dysregulates IFN-γ-inducible gene expression in human fibroblasts:: Insights from a genome-wide transcriptional profiling
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DOI：
10.4049/jimmunol.178.8.5154
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发表时间：
2007-04-15
影响因子：
4.4
通讯作者：
Boothroyd, John C.
中科院分区：
文献类型：
--
作者：
Kim, Seon-Kyeong;Fouts, Ashley E.;Boothroyd, John C.
刚地弓形虫是一种专性细胞内寄生虫，在哺乳动物宿主的生命中持续存在。弓形虫阻断ifn - γ反应的能力可能是允许弓形虫持续存在的关键机制之一。利用全基因组微阵列分析，我们在这里展示了感染弓形虫的人成纤维细胞中ifn - γ诱导基因表达的完全失调。值得注意的是，在感染细胞暴露于ifn - γ之前，127个ifn - γ应答基因中有46个被诱导，19个被抑制，这表明感染过程中产生的其他刺激也可能调节这些基因。在ifn - γ治疗后，127个ifn - γ应答基因中没有一个能在感染细胞中被显著诱导。免疫荧光分析显示，在单细胞水平上，无论使用哪种弓形虫菌株，感染的细胞都不能被IFN- γ激活来上调IFN调节因子1的表达，IFN调节因子1是一种受STAT1直接控制的转录因子，而在同一培养中未感染的细胞在IFN- γ的作用下正常表达IFN调节因子1。在ifn - γ处理的所有未感染和感染细胞中，STAT1正常且难以区分地转运到细胞核，这表明弓形虫感染的抑制作用可能是通过阻断细胞核中STAT1的转录活性来实现的。相反，一种密切相关的顶复合体，犬新孢子虫，不能抑制ifn - γ诱导的基因表达。干扰ifn - γ反应的不同能力可能在一定程度上解释了弓形虫和新孢子虫寄生虫菌株之间发病机制的差异。
Toxoplasma gondii is an obligate intracellular parasite that persists for the life of a mammalian host. The parasite's ability to block the potent IFN-gamma response may be one of the key mechanisms that allow Toxoplasma to persist. Using a genome-wide microarray analysis, we show here a complete dysregulation of IFN-gamma-inducible gene expression in human fibroblasts infected with Toxoplasma. Notably, 46 of the 127 IFN-gamma-responsive genes were induced and 19 were suppressed in infected cells before they were exposed to IFN-gamma, indicating that other stimuli produced during infection may also regulate these genes. Following IFN-gamma treatment, none of the 127 IFN-gamma-responsive genes could be significantly induced in infected cells. Immunofluorescence assays showed at single-cell levels that infected cells, regardless of which Toxoplasma strain was used, could not be activated by IFN-gamma to up-regulate the expression of IFN regulatory factor 1, a transcription factor that is under the direct control of STAT1, whereas uninfected cells in the same culture expressed IFN regulatory factor 1 normally in response to IFN-gamma. STAT1 trafficked to the nucleus normally and indistinguishably in all uninfected and infected cells treated with IFN-gamma indicating that the inhibitory effects of Toxoplasma infection likely occur via blocking STAT1 transcriptional activity in the nucleus. In contrast, a closely related apicomplexan, Neospora caninum, was unable to inhibit IFN-gamma-induced gene expression. A differential ability to interfere with the IFN-gamma response may, in part, account for the differences in the pathogenesis seen among Toxoplasma and Neospora parasite strains.