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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.

项目总结