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

耶尔森菌对 Toll 样受体控制的生命和死亡信号的放松管制

• 批准号: 85480600
• 负责人: Professor Dr. Klaus Ruckdeschel
• 金额: --
• 依托单位: Institut für Medizinische Mikrobiologie, Virologie und Hygiene
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/85480600?language=en
• 关键词: Deregulation; Toll; like; receptor; controlled

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.

先天免疫细胞对微生物感染的反应受复杂的调节途径控制。被微生物损害的宿主细胞可能发出炎症信号并存活，或经历具有不同结果的细胞死亡。然而，控制不同反应活化的细胞机制却定义不清。我们以前的研究结果表明，革兰氏阴性肠致病菌Y。小肠结肠炎靶向Toll样受体（TLR）诱导的信号传导途径，以触发巨噬细胞凋亡。TLR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。我们希望利用耶尔森菌作为工具，剖析受感染巨噬细胞中TLR 4下游的生与死信号。为此，耶尔森氏菌毒力蛋白改变TLR信号级联中的两个中心衔接蛋白RIP1和MyD88的结构、功能和募集的分子机制将被表征。其目的是指定在微生物挑战时指示巨噬细胞从细胞存活到受控凋亡和坏死的转换的调节途径。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可能影响宿主免疫的细胞死亡诱导或调节药物提供基础，但也可以影响组织稳态和肿瘤发生。