Defining the mechanism and functions of RIPK1-induced cell death in anti-bacterial immune defense

明确RIPK1诱导细胞死亡在抗菌免疫防御中的机制和功能

基本信息

批准号：
10329911
负责人：
IGOR E BRODSKY
金额：
$ 56.53万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10329911
关键词：
Address Anti-Bacterial Agents Antibiotic Resistance Bacteria Bacterial Infections Biological Assay CASP1 gene CASP8 gene Caspase Cell Death Cell Death Induction Cells Cessation of life Complex Cytolysis Data Disease Exposure to Foundations Gastroenteritis Granuloma HMGB1 gene Host Defense Immune Immune response Immune signaling Immunity Immunologics Infection Infection Control Inflammation Mediators Inflammatory Injections Interleukin-1 Interleukin-18 Knock-in Mouse Knowledge Lead Lesion MAP Kinase Gene MAPK Signaling Pathway Pathway Mediating Microbiology Modification Molecular Mus Pasteurella pseudotuberculosis Pathogenicity Pathologic Pathway interactions Pharmacology Phenocopy Phosphorylation Phosphotransferases Plague Population Post-Translational Protein Processing Production Protein Kinase Proteins Publishing RIPK1 gene Receptor Signaling Reporter Reporting Resistance Rodent Role Serine Signal Pathway Signal Transduction Stimulus Structure System TNF gene TNFRSF1A gene Testing Therapeutic Time Tissues Toll-like receptors Tumor Necrosis Factor Receptor VDAC1 gene Virulence Factors Virulent Y base Yersinia Yersinia infections Yersinia pestis cell type cytokine defined contribution genetic regulatory protein in vivo insight kinase inhibitor macrophage neutrophil next generation novel pathogen pathogenic microbe prevent public health relevance receptor function recruit resistant strain response

项目摘要

Project Summary Immune defense against bacterial infection requires signaling pathways that activate expression of inflammatory mediators to control and clear infection. Many pathogens inhibit these signaling pathways in order to evade host immune defenses. In particular, Yersinia injects a virulence factor, YopJ, which potently blocks key aspects of NF-ΚB and MAPK signaling pathways. How immune defense is mediated against pathogens that block immune signaling pathways remains poorly understood. NF-κB blockade in macrophages exposed to bacterial PAMPs leads to cell death. Importantly, our recently published data demonstrate that RIPK1 kinase activity is required for Yersinia-induced cell death, and that RIPK1 kinase activity is critical for resistance to Yersinia infection and innate inflammatory cytokine production in vivo. This suggests that RIPK1- induced death triggered by Yersinia is a key immune protective mechanism. Our new studies indicate that IKK phosphorylates RIPK1 to limit induction of cell death by inflammatory stimuli, suggesting that Yersinia blockade of IKK releases RIPK1 from this inhibitory effect. How RIPK1 kinase activity and cell death promote host defense against bacterial infection is not known. Our central hypothesis is that RIPK1-mediated cell death triggered in response to pathogen-mediated NF-κB and MAPK blockade releases pro-inflammatory signals, such as IL-1 cytokines and intracellular alarmins that enable uninfected bystander cells to produce key inflammatory mediators such as TNF, which control infection by pathogens that interfere with innate signaling. This is an important problem as this pathway likely responds to many pathogens that block critical innate immune signaling pathways and in the context of pathological stimuli that lead to RIPK1-induced cell death. We propose three Specific Aims to address this important gap in our knowledge. First we will define the molecular basis for how RIPK1 kinase activation occurs in response to YopJ blockade of IKK signaling, and test the role of this pathway in anti-bacterial immune defense. Second, we will define immune responses of infected and bystander cells, and will define the contribution of RIPK1-dependent cell death pathways to anti- bacterial host defense in vivo. Finally, we will determine the contribution of TNF signaling by bystander cells to antibacterial immune defense and will define the cell-type specific requirement for RIPK1- and TNFR- dependent cell death in host immune defense against Yersinia.

项目摘要免疫防御细菌感染需要信号通路，以激活的表达炎症介质控制和清除感染。许多病原体抑制这些信号通路为了逃避主机免疫防御。特别是，耶尔森氏症注射病毒因子YopJ，它可能有可能阻止NF-κB和MAPK信号通路的关键方面。免疫防御是如何介导的阻断免疫信号通路的病原体仍然了解不足。巨噬细胞中的NF-κB封锁暴露于细菌症状会导致细胞死亡。重要的是，我们最近发布的数据表明 RIPK1激酶活性是耶尔森尼亚诱导的细胞死亡所必需的，RIPK1激酶活性对于体内对耶尔森氏菌感染和先天炎症细胞因子产生的抗性。这表明Ripk1- Yersinia触发的诱导死亡是一种关键的免疫保护机制。我们的新研究表明IKK 磷酸化RIPK1以限制炎症刺激对细胞死亡的诱导，这表明Yersinia封锁 IKK的释放从这种抑制作用中释放出来。 RIPK1激酶活性和细胞死亡如何促进宿主对细菌感染的防御尚不清楚。我们的中心假设是RIPK1介导的细胞死亡响应病原体介导的NF-κB和MAPK封锁释放促炎信号，触发，例如IL-1细胞因子和细胞内警报，使未感染的旁观者细胞产生钥匙炎症介质（例如TNF）控制着干扰先天信号的病原体感染。这是一个重要的问题，因为该途径可能会响应许多阻碍关键先天的病原体免疫信号通路和在病理刺激的背景下导致RIPK1诱导的细胞死亡。我们提出了三个特定的目标，以解决我们知识的这一重要差距。首先，我们将定义 RIPK1激酶激活如何响应IKK信号的YOPJ阻断和测试该途径在抗细菌免疫防御中的作用。其次，我们将定义免疫反应感染和旁观者细胞，并将定义RIPK1依赖性细胞死亡途径对抗 - 细菌宿主防御在体内。最后，我们将确定旁观者细胞对TNF信号的贡献抗菌免疫防御，并将定义RIPK1和TNFR-的细胞类型特异性需求宿主免疫防御耶尔森氏菌的依赖细胞死亡。