Dissecting the mechanism of RIPK1 kinase-dependent cell death in control of Yersinia infection

剖析 RIPK1 激酶依赖性细胞死亡控制耶尔森菌感染的机制

• 批准号: 9285729
• 负责人: IGOR E BRODSKY
• 金额: $ 20.86万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-06 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9285729
• 关键词: Address; Alpha Cell; Anti-Bacterial Agents; Apoptosis; Bacterial Infections; Bone Marrow; CASP8 gene; Cell Death; Cell Death Induction; Cells; Cessation of life; Characteristics; Complex; Coupled; Cytotoxic T-Lymphocytes; Data; Defect; Disease; Ensure; Enzymes; Foundations; Future; Gastroenteritis; Goals; Hematopoietic; Host Defense; Immune; Immune response; Immune signaling; Immunity; Infection; Inflammation Mediators; Inflammatory; Inflammatory Response; Injectable; Innate Immune Response; Instruction; Interferon Type II; Interleukin-12; Knowledge; Lead; Light; Lymphocyte; MAP Kinase Gene; Mediating; Molecular; Mus; Pasteurella pseudotuberculosis; Pathogenicity; Pathologic; Pathway interactions; Phosphotransferases; Plague; Play; Population; Production; Protein Kinase; Publishing; RIPK1 gene; Role; Signal Pathway; Signal Transduction; Stimulus; T cell response; TNF gene; Testing; Time; Tissues; Toll-like receptors; Virulence; Virulence Factors; Yersinia; Yersinia infections; Yersinia pestis; adaptive immune response; antimicrobial; base; cell type; cytokine; cytotoxicity; defined contribution; extracellular; in vivo; insight; macrophage; microbial; monocyte; mutant; novel; oral infection; pathogen; public health relevance; receptor; response

Project Summary Immune defense against bacterial infection requires activation of conserved signaling pathways that upregulate production of inflammatory mediators to clear infection. Many pathogens, including the pathogenic Yersinia inhibit these signaling pathways in order to evade host immune defenses. Yersinia injects a virulence factor, YopJ, which blocks NF-ΚB and MAPK signaling. 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 with characteristics of apoptosis, yet this death has pro-inflammatory consequences. Notably, increasing cytotoxicity of Y. pseudotuberculosis or Y. pestis results in decreased bacterial virulence, suggesting that induction of cell death in response to Yersinia serves as a host immune protective mechanism. Our central hypothesis is that cell death triggered in response to Yersinia blockade of NF-κB and MAPK releases pro-inflammatory signals that alert uninfected neighboring cells to the presence of infection. However, the cellular and molecular basis for this response remains unclear. Our recently published and preliminary data demonstrate that RIPK1 kinase activity is required for Yersinia-induced cell death. Moreover, RIPK1 kinase activity contributes to control of Yersinia infection and to inflammatory cytokine production in vivo. Nevertheless, how RIPK1 kinase activity and cell death are coupled to inflammatory responses and host defense against bacterial infection is not known. 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 two Specific Aims to address this important gap in our knowledge. First we will define the cellular population that requires RIPK1 kinase activity, and determine whether RIPK1 functions in a cell-intrinsic or extrinsic manner to mediate anti-bacterial immune defense. Second, we will will determine the contribution of RIPK1 to downstream pathogen-specific immune responses and will dissect whether RIPK1 functions to control bacterial dissemination or replication.

项目摘要 免疫防御细菌感染需要激活更新的配置信号通路 产生炎症介质以清除感染。许多病原体，包括病原耶尔森氏菌 抑制这些信号通路以逃避宿主免疫防御。 Yersinia注射病毒因子， YOPJ，阻断NF-κB和MAPK信号传导。如何针对病原体介导免疫诱因 阻止免疫信号通路仍然了解不足。巨噬细胞中的NF-κB封锁 细菌症状症状导致细胞死亡，并具有细胞凋亡的特征，但这种死亡具有促炎症 结果。值得注意的是，Y. pseudotuberculculosis或Y. Pestis的细胞毒性增加导致下降 细菌病毒，表明对耶尔森氏菌的诱导诱导可作为宿主免疫 保护机制。我们的中心假设是，响应于Yersinia封锁的细胞死亡 NF-κB和MAPK释放促炎性信号，使未感染的相邻细胞警告出现 感染。但是，该反应的细胞和分子基础尚不清楚。我们最近出版的 初步数据表明，耶尔森尼亚诱导的细胞死亡需要RIPK1激酶活性。 此外，RIPK1激酶活性有助于控制耶尔森氏菌感染和炎性细胞因子 体内生产。然而，RIPK1激酶活性和细胞死亡如何与炎症耦合 反应和宿主防御细菌感染尚不清楚。这是一个重要的问题 途径可能会响应许多阻断关键先天免疫信号通路和在 导致RIPK1诱导细胞死亡的病理刺激的背景。我们提出了两个特定的目的来解决 我们知识上的这一重要差距。首先，我们将定义需要RIPK1激酶的细胞群 活性，并确定RIPK1是否以细胞中的或外在的方式起作用以介导抗细菌 免疫防御。其次，我们将确定RIPK1对下游病原体特异性的贡献 免疫反应，并将剖析RIPK1是否功能控制细菌传播或复制。