Laboratory of Immunology and Microbial Pathogenesis, National Institute of Animal Biotechnology, Hyderabad, Telangana, India; Centre for Biotechnology, Institute of Science and Technology, Jawaharlal Nehru Technological University, Hyderabad, India.
Laboratory of Immunology and Microbial Pathogenesis, National Institute of Animal Biotechnology, Hyderabad, Telangana, India; Regional Centre for Biotechnology (RCB), Faridabad, India.
J Biol Chem. 2023 Nov;299(11):105309. doi: 10.1016/j.jbc.2023.105309. Epub 2023 Sep 29.
Toll-like receptors (TLRs) are essential components of innate immunity that serves as the first line of defense against the invaded microorganisms. However, successful infectious pathogens subvert TLR signaling to suppress the activation of innate and adaptive responses. Brucella species are infectious intracellular bacterial pathogens causing the worldwide zoonotic disease, brucellosis, that impacts economic growth of many countries. Brucella species are considered as stealthy bacterial pathogens as they efficiently evade or suppress host innate and adaptive immune responses for their chronic persistence. However, the bacterial effectors and their host targets for modulating the immune responses remain obscure. Brucella encodes various outer membrane proteins (Omps) that facilitate their invasion, intracellular replication, and immunomodulation. Outer membrane protein 25 (Omp25) of Brucella plays an important role in the immune modulation through suppression of proinflammatory cytokines. However, the mechanism and the signaling pathways that are targeted by Omp25 to attenuate the production of proinflammatory cytokines remain obscure. Here, we report that Omp25 and its variants, viz. Omp25b, Omp25c, and Omp25d, suppress production of proinflammatory cytokines that are mediated by various TLRs. Furthermore, we demonstrate that Omp25 and its variants promote enhanced ubiquitination and degradation of TLRs and their adaptor proteins to attenuate the expression of proinflammatory cytokines. Targeting multiple TLRs and adaptor proteins enables Omp25 to effectively suppress the expression of proinflammatory cytokines that are induced by diverse pathogen-associated molecular patterns. This can contribute to the defective adaptive immune response and the chronic persistence of Brucella in the host.
toll 样受体 (TLRs) 是先天免疫的重要组成部分，作为抵御入侵微生物的第一道防线。然而，成功的传染性病原体颠覆了 TLR 信号转导，抑制了先天和适应性反应的激活。布鲁氏菌属是引起世界范围内动物传染病布鲁氏菌病的传染性细胞内细菌病原体，影响许多国家的经济增长。布鲁氏菌属被认为是隐秘的细菌病原体，因为它们能够有效地逃避或抑制宿主先天和适应性免疫反应，从而实现慢性持续存在。然而，细菌效应物及其宿主靶标用于调节免疫反应仍不清楚。布鲁氏菌属编码各种外膜蛋白 (Omps)，这些蛋白有助于其入侵、细胞内复制和免疫调节。布鲁氏菌的外膜蛋白 25 (Omp25) 通过抑制促炎细胞因子在免疫调节中发挥重要作用。然而，Omp25 靶向的机制和信号通路以减弱促炎细胞因子的产生仍不清楚。在这里，我们报告 Omp25 及其变体，即 Omp25b、Omp25c 和 Omp25d，抑制各种 TLR 介导的促炎细胞因子的产生。此外，我们证明 Omp25 及其变体促进 TLR 和其衔接蛋白的增强泛素化和降解，以减弱促炎细胞因子的表达。靶向多个 TLR 和衔接蛋白使 Omp25 能够有效地抑制由各种病原体相关分子模式诱导的促炎细胞因子的表达。这有助于适应性免疫反应的缺陷和布鲁氏菌在宿主中的慢性持续存在。
