Crosstalk between Signaling Processes of Innate Immunity and Yersinia YopP Effector Functions

肠源性耶尔森氏菌已经进化出多种策略来干扰宿主的免疫反应，这使得宿主淋巴组织中的细菌能够在细胞外繁殖。耶尔森氏菌免疫调节的一个显著特征是诱导巨噬细胞的凋亡。耶尔森氏菌利用III型蛋白分泌系统，将许多毒力因子，即所谓的YOPs，转移到宿主细胞细胞质内。其中YOPP以核因子-kB激活蛋白IKKB为靶点，抑制转录因子核因子-kB的激活，抑制依赖于核因子-kB的抗细胞凋亡活性。耶尔森氏菌感染或内毒素处理同时启动促凋亡信号，导致巨噬细胞凋亡。因此，耶尔森氏菌利用先天免疫机制来调节巨噬细胞的死亡。在目前的项目中，我们想要表征先天免疫的信号过程对耶尔森氏菌诱导的效应器功能的影响。首先，我们想要阐明耶尔森氏菌是通过什么机制激活先天免疫的信号通路的。先天免疫的细胞毒性信号及其在耶尔森氏菌诱导的细胞凋亡中的作用将被确定。最后，我们想要在耶尔森氏菌-小鼠感染模型中表征这些发现在体内的致病意义。总之，这些数据应该揭示微生物-宿主细胞相互作用机制的新方面，并为天然免疫信号提供新的见解。

Enteropathogenic Yersinia species have evolved multiple strategies to interfere with the immune response of the host, which enables extracellular multiplication of the bacteria in the host lymphoid tissue. One outstanding feature of immune modulation by Yersinia is the induction of apoptosis in macrophages. Yersinia engages a type III protein secretion system to translocate a number of virulence factors, the so-called Yops, inside the host cell cytoplasm. One of these Yops, YopP, targets the NF-kB-activating kinase IKKb, which inhibits activation of transcription factor NF-kB and suppresses NF-kB-dependent antiapoptotic activities. The simultaneous initiation of proapoptotic signaling by Yersinia infection or LPS treatment results in macrophage apoptosis. Thus, Yersinia exploits the mechanisms of innate immunity to mediate macrophage cell death. In the current project, we want to characterize the impact of signaling processes of innate immunity on Yersinia-induced effector functions. Initially, we want to elucidate by which mechanisms Yersinia activates signaling pathways of innate immunity. The cytotoxic signals of innate immunity and their contribution to Yersinia-induced apoptosis will be determined. Finally, we want to characterize the pathogenetic significance of these findings in vivo in the Yersinia-mouse infection model. Together, this data should reveal new aspects of the mechanisms of microbe-host cell interaction and provide new insights into signaling of innate immunity.