Chlamydia trachomatis Is Resistant to Inclusion Ubiquitination and Associated Host Defense in Gamma Interferon-Primed Human Epithelial Cells.
Chlamydia trachomatis Is Resistant to Inclusion Ubiquitination and Associated Host Defense in Gamma Interferon-Primed Human Epithelial Cells.
复制标题
沙眼衣原体具有抗包容性泛素化和相关的宿主防御能力的伽玛干扰素上皮细胞。
DOI：
10.1128/mbio.01417-16
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发表时间：
2016-12-13
期刊：
影响因子：
6.4
通讯作者：
Coers J
中科院分区：
文献类型：
--
作者：
Haldar AK;Piro AS;Finethy R;Espenschied ST;Brown HE;Giebel AM;Frickel EM;Nelson DE;Coers J
细胞因子γ干扰素（IFN-γ）诱导细胞自主免疫对抗细胞内病原体感染，如沙眼衣原体。本研究表明，IFN-γ引发的人类细胞泛素化并消除细胞内含有衣原体的液泡，即所谓的内含物。我们之前描述了IFN-γ诱导的免疫相关GTPases （IRGs）如何利用泛素系统在小鼠细胞中标记包涵体以进行破坏，并且进一步表明啮齿动物病原体muridarum衣原体通过干扰小鼠IRG功能来阻断其包涵体的泛素化。在这里，我们报告了人类细胞中包涵体的泛素化是独立于IRG的，因此与小鼠途径不同。我们发现，在人类细胞中，muridarum对包涵泛素化很敏感，而与之密切相关的人类病原体沙眼衣原体则具有耐药性。沙眼衣原体的包涵体可吸引几种细胞自主免疫标记物，包括泛素结合蛋白p62、泛素样蛋白LC3和鸟苷结合蛋白1。因此，我们发现IFN-γ对人上皮细胞的启动可触发去除沙眼衣原体，而非沙眼衣原体内含物。这种新描述的防御途径不依赖于吲哚-2,3-双加氧酶，这是一种已知的IFN-γ诱导的抗衣原体抗性因子。总的来说，我们的观察表明，沙眼衣原体进化出了避免人类特异性泛素介导反应的机制，这是其对人类宿主的独特适应的一部分。沙眼衣原体是性传播细菌感染的主要原因，并导致严重的发病率，包括盆腔炎、不孕和女性异位妊娠。作为一种专性细胞内病原体，沙眼衣原体与人类宿主的细胞内在防御程序处于永久冲突中。我们的研究确定了一种在人上皮细胞中活跃的新的抗衣原体宿主抗性途径。这个防御程序促进了小抗菌蛋白泛素在含有衣原体的液泡上的沉积。我们表明，这种基于泛素的人类细胞抗性途径对适应啮齿动物的衣原体物种非常有效，但对适应人类的沙眼衣原体无效。这一观察结果表明，沙眼衣原体进化出了避免被困在泛素标记的液泡中的策略，这是其对人类先天免疫系统的适应的一部分。
The cytokine gamma interferon (IFN-γ) induces cell-autonomous immunity to combat infections with intracellular pathogens, such as the bacterium Chlamydia trachomatis. The present study demonstrates that IFN-γ-primed human cells ubiquitinate and eliminate intracellular Chlamydia-containing vacuoles, so-called inclusions. We previously described how IFN-γ-inducible immunity-related GTPases (IRGs) employ ubiquitin systems to mark inclusions for destruction in mouse cells and, furthermore, showed that the rodent pathogen Chlamydia muridarum blocks ubiquitination of its inclusions by interfering with mouse IRG function. Here, we report that ubiquitination of inclusions in human cells is independent of IRG and thus distinct from the murine pathway. We show that C. muridarum is susceptible to inclusion ubiquitination in human cells, while the closely related human pathogen C. trachomatis is resistant. C. muridarum, but not C. trachomatis, inclusions attract several markers of cell-autonomous immunity, including the ubiquitin-binding protein p62, the ubiquitin-like protein LC3, and guanylate-binding protein 1. Consequently, we find that IFN-γ priming of human epithelial cells triggers the elimination of C. muridarum, but not C. trachomatis, inclusions. This newly described defense pathway is independent of indole-2,3-dioxygenase, a known IFN-γ-inducible anti-Chlamydia resistance factor. Collectively, our observations indicate that C. trachomatis evolved mechanisms to avoid a human-specific, ubiquitin-mediated response as part of its unique adaptation to its human host. Chlamydia trachomatis is the leading cause of sexually transmitted bacterial infections and responsible for significant morbidity, including pelvic inflammatory disease, infertility, and ectopic pregnancies in women. As an obligate intracellular pathogen, C. trachomatis is in perpetual conflict with cell-intrinsic defense programs executed by its human host. Our study defines a novel anti-Chlamydia host resistance pathway active in human epithelial cells. This defense program promotes the deposition of the small antimicrobial protein ubiquitin on vacuoles containing Chlamydia. We show that this ubiquitin-based resistance pathway of human cells is highly effective against a Chlamydia species adapted to rodents but ineffective against human-adapted C. trachomatis. This observation indicates that C. trachomatis evolved strategies to avoid entrapment within ubiquitin-labeled vacuoles as part of its adaptation to the human innate immune system.