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

肠致病性耶尔森氏菌已经进化出多种策略来干扰宿主的免疫应答，这使得细菌在宿主淋巴组织中的细胞外增殖成为可能。耶尔森氏菌免疫调节的一个突出特征是诱导巨噬细胞凋亡。耶尔森氏菌利用III型蛋白分泌系统在宿主细胞质内易位许多毒力因子，即所谓的Yops。其中一种Yops，YopP，靶向NF-κ B激活激酶IKKb，其抑制转录因子NF-κ B的激活并抑制NF-κ B依赖性抗凋亡活性。耶尔森氏菌感染或LPS处理引起的促凋亡信号的同时启动导致巨噬细胞凋亡。因此，耶尔森氏菌利用先天免疫机制介导巨噬细胞死亡。在目前的项目中，我们希望表征先天免疫信号传导过程对耶尔森氏菌诱导的效应器功能的影响。首先，我们想阐明耶尔森菌激活先天免疫信号通路的机制。将确定先天免疫的细胞毒性信号及其对耶尔森氏菌诱导的细胞凋亡的贡献。最后，我们希望在耶尔森氏菌-小鼠感染模型中描述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，并为先天免疫信号转导提供新的见解。

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.