Deregulation of Toll-like receptor-controlled life and death signals by Yersinia

先天免疫细胞对微生物感染的反应受复杂的调控途径控制。被微生物破坏的宿主细胞可能发出炎症信号并存活，或者经历不同结果的细胞死亡。然而，控制不同反应激活的细胞机制还不清楚。我们先前的研究结果表明，革兰氏阴性肠道病原菌小肠结肠炎耶尔森菌以Toll样受体(TLR)诱导的信号通路为靶点，触发巨噬细胞的凋亡。TLRs是引起炎症的微生物感染的中心传感器，但它们也可能发出不同形式的细胞死亡信号。我们想用耶尔森氏菌作为工具来剖析TLR4下游受感染巨噬细胞的生死信号。为此，我们将对耶尔森氏菌毒力蛋白改变RIP1和MyD88的结构、功能和募集的分子机制进行研究，RIP1和MyD88是TLR信号级联中的两个中心接头蛋白。这项研究的目的是明确巨噬细胞在微生物攻击下从细胞存活到可控的凋亡和坏死的调控途径。更好地了解先天免疫反应中程序性死亡的信号网络，可以为开发细胞死亡诱导或调节药物提供基础，这些药物可能影响宿主免疫，也可能影响组织动态平衡和肿瘤发生。

The response of innate immune cells to microbial infection is controlled by complex regulatory pathways. A host cell compromised by a microbe may signal inflammation and survive, or undergo cell death with different outcome. The cellular mechanisms that govern the activation of the distinct reactions are, however, poorly defined. Our previous results have shown that the gram-negative enteropathogenic bacterium Y. enterocolitica targets Toll-like receptor (TLR)-induced signaling pathways to trigger apoptosis in macrophages. TLRs are central sensors of microbial infection that elicit inflammation, but they may also signal different forms of cellular death. We want to use Yersinia as tool to dissect the signals of life and death downstream from TLR4 in infected macrophages. For this purpose, the molecular mechanisms by which Yersinia virulence proteins alter structure, function and recruitment of RIP1 and MyD88, two central adapter proteins within the TLR signaling cascade, will be characterized. This aims to specify the regulatory paths that dictate the switch from cell survival to controlled apoptosis and necrosis in macrophages upon microbial challenge. A better understanding of the signaling networks of programmed death in the innate immune response could provide a basis for the development of cell death-inducing or -modulating drugs that may influence host immunity, but also tissue homeostasis and tumorigenesis.