Chlamydia-driven ISG15 expression dampens the immune response of epithelial cells independently of ISGylation.

IF 5.1 1区 生物学 Q1 MICROBIOLOGY mBio Pub Date : 2024-11-13 Epub Date: 2024-09-30 DOI:10.1128/mbio.02401-24
Yongzheng Wu, Chang Liu, Chongfa Tang, Béatrice Niragire, Yaël Levy-Zauberman, Cindy Adapen, Thomas Vernay, Juliette Hugueny, Véronique Baud, Agathe Subtil
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Abstract

Excessive inflammation upon Chlamydia trachomatis infection can cause severe damages in the female genital tract. This obligate intracellular bacterium develops mainly in epithelial cells, whose innate response contributes to the overall inflammatory response to infection. The ubiquitin-like protein interferon-stimulated gene 15 (ISG15) stimulates interferon γ (IFNγ) production and is required for bacterial clearance in several infectious contexts. Here, we describe and investigate the consequences of the increase in ISG15 expression by epithelial cells infected with C. trachomatis. Infection of HeLa cells and primary ecto-cervical epithelial cells resulted in a transcriptional upregulation of ISG15 expression. This did not involve the canonical type I interferon (IFN-I) signaling pathway and depended instead on the activation of the STING/TBK1/IRF3 pathway. The absence or reduction of ISG15 synthesis led to increased production of several cytokines and chemokines, including interleukin (IL) 6 and IL8. This implicates that ISG15 normally dampens the immune response induced by C. trachomatis infection in epithelial cells. ISG15 exerted its control from an intracellular location, but without involving ISGylation. Finally, higher levels of inflammation and delayed bacterial clearance were observed in the genital tracts of ISG15-KO mice infected by C. trachomatis compared with wild-type animals; however, IFNγ production was unchanged. Altogether, our data show that ISG15 expression acts as a brake on the immune response to C. trachomatis infection in epithelial cells and limits bacterial burden and inflammation in mice.IMPORTANCEInfection of epithelial cells by Chlamydia trachomatis elicits an innate immune response by these cells. The signaling pathways involved, and their outcomes, are still very poorly understood. In this paper, we described how Chlamydia infection triggered the expression of ISG15, a small molecule normally associated to type I interferon (IFN-I) signaling and control of INF-γ production. ISG15 synthesis by epithelial cells attenuated their immune response to Chlamydia infection. In mice, we observed that ISG15 displayed a marginal role in modulating the production of IFN-γ, a key component of the host immune response to infection, but facilitated bacterial clearance. Overall, our study strengthens the importance of ISG15 not only in the resolution of viral but also of bacterial infection and document its role of "immune brake" in the context of Chlamydia infection.

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衣原体驱动的 ISG15 表达可抑制上皮细胞的免疫反应,而与 ISGylation 无关。
沙眼衣原体感染引起的过度炎症可对女性生殖道造成严重损害。这种固有的细胞内细菌主要在上皮细胞中生长,而上皮细胞的先天性反应促成了对感染的整体炎症反应。泛素样蛋白干扰素刺激基因 15(ISG15)能刺激干扰素 γ(IFNγ)的产生,在多种感染情况下都需要它来清除细菌。在这里,我们描述并研究了感染沙眼衣原体的上皮细胞 ISG15 表达增加的后果。感染 HeLa 细胞和原代宫颈上皮细胞会导致 ISG15 表达的转录上调。这并不涉及典型的I型干扰素(IFN-I)信号通路,而是取决于STING/TBK1/IRF3通路的激活。ISG15 合成的缺失或减少会导致包括白细胞介素(IL)6 和 IL8 在内的多种细胞因子和趋化因子的生成增加。这表明 ISG15 通常会抑制沙眼衣原体感染上皮细胞所诱导的免疫反应。ISG15 从细胞内位置发挥控制作用,但不涉及 ISGylation。最后,与野生型小鼠相比,ISG15-KO 小鼠感染沙眼衣原体后生殖道的炎症程度更高,细菌清除时间更晚;但 IFNγ 的产生没有变化。重要意义沙眼衣原体感染上皮细胞会引起这些细胞的先天性免疫反应。人们对其中涉及的信号通路及其结果仍知之甚少。在本文中,我们描述了衣原体感染如何触发 ISG15 的表达,ISG15 是一种通常与 I 型干扰素(IFN-I)信号传导和 INF-γ 生成控制相关的小分子。上皮细胞合成 ISG15 可减轻它们对衣原体感染的免疫反应。在小鼠中,我们观察到 ISG15 在调节宿主对感染的免疫反应的关键成分 IFN-γ 的产生方面发挥了微不足道的作用,但却促进了细菌的清除。总之,我们的研究加强了 ISG15 在解决病毒感染和细菌感染中的重要性,并证明了它在衣原体感染中的 "免疫制动器 "作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
mBio
mBio MICROBIOLOGY-
CiteScore
10.50
自引率
3.10%
发文量
762
审稿时长
1 months
期刊介绍: mBio® is ASM''s first broad-scope, online-only, open access journal. mBio offers streamlined review and publication of the best research in microbiology and allied fields.
期刊最新文献
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