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 针对细菌感染的免疫防御需要激活保守的信号通路来上调 产生炎症介质以清除感染。许多病原体，包括致病性耶尔森氏菌 抑制这些信号通路以逃避宿主的免疫防御。耶尔森氏菌注入一种毒力因子， YopJ，其阻断NF-ΚB B和MAPK信号传导。免疫防御是如何介导的， 阻断免疫信号通路仍然知之甚少。巨噬细胞NF-κB的阻断作用 细菌PAMPs导致具有凋亡特征的细胞死亡，但这种死亡具有促炎性， 后果显著增加Y. pseudotuberculosis或Y.鼠疫导致 细菌的毒力，表明诱导细胞死亡的反应耶尔森菌作为宿主免疫 保护机制我们的中心假设是，细胞死亡是由耶尔森氏菌对细胞的阻断引起的。 NF-κB和MAPK释放促炎信号，警告未感染的邻近细胞存在 感染然而，这种反应的细胞和分子基础仍不清楚。我们最近出版的 初步数据表明，RIPK 1激酶活性是耶尔森氏菌诱导的细胞死亡所必需的。 此外，RIPK 1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，RIPK 1激酶活性和细胞死亡如何与炎症反应相关， 对细菌感染的反应和宿主防御尚不清楚。这是一个重要的问题， 途径可能对许多阻断关键先天免疫信号传导途径的病原体做出反应， 导致RIPK 1诱导的细胞死亡的病理刺激的背景。我们提出两个具体目标，以解决 这是我们知识中的一个重要缺口。首先，我们将确定需要RIPK 1激酶的细胞群体 活性，并确定RIPK 1是否以细胞内源性或外源性方式介导抗细菌 免疫防御其次，我们将确定RIPK 1对下游病原体特异性免疫应答的贡献。 免疫反应，并将剖析是否RIPK 1的功能，以控制细菌传播或复制。