Cellular Biology of Microbial Infection, Institut Pasteur, Université Paris Cité, CNRS UMR3691, Paris, France.
National Vaccine and Serum Institute, Beijing, China.
mBio. 2024 Nov 13;15(11):e0240124. doi: 10.1128/mbio.02401-24. Epub 2024 Sep 30.
Excessive inflammation upon 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 . Infection of HeLa cells and primary ecto-cervical epithelial cells resulted in a transcriptional upregulation of 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 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 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 infection in epithelial cells and limits bacterial burden and inflammation in mice.IMPORTANCEInfection of epithelial cells by 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 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 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 infection.
感染时过度的炎症会对女性生殖道造成严重损害。这种专性细胞内细菌主要在上皮细胞中发育，其先天反应有助于感染的整体炎症反应。泛素样蛋白干扰素刺激基因 15（ISG15）刺激干扰素 γ（IFNγ）的产生，并在几种感染情况下清除细菌。在这里，我们描述并研究了被感染的上皮细胞中 ISG15 表达增加的后果。HeLa 细胞和原代宫颈上皮细胞的感染导致表达的转录上调。这并不涉及经典的 I 型干扰素（IFN-I）信号通路，而是依赖于 STING/TBK1/IRF3 途径的激活。ISG15 的缺失或减少导致包括白细胞介素（IL）6 和 IL8 在内的几种细胞因子和趋化因子的产生增加。这表明 ISG15 通常会抑制上皮细胞中感染引起的免疫反应。ISG15 从细胞内位置发挥其控制作用，但不涉及 ISG 化。最后，与野生型动物相比，感染的 ISG15-KO 小鼠生殖道中观察到更高水平的炎症和延迟的细菌清除；然而，IFNγ 的产生没有改变。总的来说，我们的数据表明，ISG15 的表达在上皮细胞感染中的作用是对免疫反应的制动，并限制了小鼠的细菌负担和炎症。
重要性
上皮细胞被感染会引发这些细胞的先天免疫反应。涉及的信号通路及其结果仍知之甚少。在本文中，我们描述了感染如何触发 ISG15 的表达，ISG15 是一种与 I 型干扰素（IFN-I）信号和 INF-γ 产生的控制相关的小分子。上皮细胞中 ISG15 的合成减弱了它们对感染的免疫反应。在小鼠中，我们观察到 ISG15 在调节 IFN-γ的产生方面发挥了微不足道的作用，IFN-γ是宿主对感染免疫反应的关键组成部分，但促进了细菌清除。总的来说，我们的研究加强了 ISG15 不仅在病毒感染的消退中而且在细菌感染中的重要性，并证明了它在感染背景下作为“免疫刹车”的作用。
