Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte 30270-901, Brazil.
Departamento de Microbiologia, Imunologia e Parasitologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianopolis, Santa Catarina 88040-900, Brazil.
J Immunol. 2019 May 1;202(9):2671-2681. doi: 10.4049/jimmunol.1801233. Epub 2019 Mar 20.
is a facultative intracellular bacterium that causes brucellosis, a prevalent zoonosis that leads to abortion and infertility in cattle, and undulant fever, debilitating arthritis, endocarditis, and meningitis in humans. Signaling pathways triggered by involves stimulator of IFN genes (STING), which leads to production of type I IFNs. In this study, we evaluated the pathway linking the unfolded protein response (UPR) and the endoplasmic reticulum-resident transmembrane molecule STING, during infection. We demonstrated that infection induces the expression of the UPR target gene and in murine macrophages through a STING-dependent pathway. Additionally, we also observed that STING activation was dependent on the bacterial second messenger cyclic dimeric GMP. Furthermore, the -induced UPR is crucial for induction of multiple molecules linked to type I IFN signaling pathway, such as IFN-β, IFN regulatory factor 1, and guanylate-binding proteins. Furthermore, IFN-β is also important for the UPR induction during infection. Indeed, IFN-β shows a synergistic effect in inducing the IRE1 axis of the UPR. In addition, priming cells with IFN-β favors survival in macrophages. Moreover, -induced UPR facilitates bacterial replication in vitro and in vivo. Finally, these results suggest that -induced UPR is triggered by bacterial cyclic dimeric GMP, in a STING-dependent manner, and that this response supports bacterial replication. In summary, association of STING and IFN-β signaling pathways with -induced UPR unravels a novel link between innate immunity and endoplasmic reticulum stress that is crucial for bacterial infection outcome.
布鲁氏菌是一种兼性细胞内细菌，可引起布鲁氏菌病，这是一种流行的人畜共患病，可导致牛流产和不孕，并导致人类出现波浪热、衰弱性关节炎、心内膜炎和脑膜炎。布鲁氏菌触发的信号通路涉及干扰素基因刺激物（STING），可导致 I 型干扰素的产生。在这项研究中，我们评估了 unfolded protein response（UPR）和内质网驻留跨膜分子 STING 之间的途径，在布鲁氏菌感染过程中。我们证明，布鲁氏菌感染通过依赖 STING 的途径诱导小鼠巨噬细胞中 UPR 靶基因 和 的表达。此外，我们还观察到 STING 激活依赖于细菌第二信使环二核苷酸 GMP。此外，-诱导的 UPR 对于诱导与 I 型 IFN 信号通路相关的多种分子至关重要，例如 IFN-β、IFN 调节因子 1 和鸟苷酸结合蛋白。此外，IFN-β 在布鲁氏菌感染过程中诱导 UPR 也很重要。事实上，IFN-β 在诱导 UPR 的 IRE1 轴方面具有协同作用。此外，用 IFN-β 预处理细胞有利于巨噬细胞中 的存活。此外，-诱导的 UPR 促进了体外和体内细菌的复制。最后，这些结果表明，细菌环二核苷酸 GMP 以 STING 依赖的方式触发 -诱导的 UPR，并且该反应支持细菌复制。总之，STING 和 IFN-β 信号通路与 -诱导的 UPR 的关联揭示了先天免疫和内质网应激之间的新联系，这对于细菌感染结果至关重要。
