Role of vimentin in influenza A-induced acute lung injury

波形蛋白在甲型流感引起的急性肺损伤中的作用

• 批准号: 8775974
• 负责人: KAREN M RIDGE
• 金额: $ 38.63万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8775974
• 关键词: Acute; Acute Lung Injury; Adult Respiratory Distress Syndrome; Alveolar; Alveolus; Binding; Blood capillaries; Cell Nucleus; Cells; Cessation of life; Cytoskeleton; Data; Development; Diffuse; Disease; Endothelium; Epidemic; Epithelial Cells; Equilibrium; Family; Genes; Growth Factor; Hospitalization; Immune response; Infection; Inflammatory; Influenza; Influenza A virus; Injury; Interferons; Interleukin-1; Interleukin-18; Intermediate Filament Proteins; Intermediate Filaments; Invaded; Laboratories; Leucine-Rich Repeat; Liquid substance; Lower Respiratory Tract Infection; Lung; Macromolecular Complexes; Mechanics; Mediating; Metabolic; Morbidity - disease rate; Mus; Mutation; Outer Mitochondrial Membrane; Patients; Phosphorylation; Play; Pneumonia; Post-Translational Protein Processing; Process; Production; Proteins; Recruitment Activity; Regulation; Reporting; Respiratory physiology; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Stimulus; Structure; Tertiary Protein Structure; Toll-like receptors; United States; Vimentin; Viral; Viral Pneumonia; Virus; Wound Healing; alveolar epithelium; base; capillary; cytokine; helicase; human IRF3 protein; in vitro Model; in vivo; interferon regulatory factor-3; lung injury; member; migration; monocyte; mortality; neutrophil; novel; pandemic disease; prevent; protein complex; protein expression; protein protein interaction; public health relevance; receptor; release factor 3; response; scaffold; transcription factor

DESCRIPTION (provided by applicant): Influenza A virus is a highly contagious virus that causes upper and lower respiratory tract infections resulting in 200,000 hospitalizations and 36,000 deaths in the United States annually, and new influenza strains generate recurring epidemics and pandemics with significant attributable morbidity and mortality. Most of the mortality associated with influenza A infection is attributable to development of the acute respiratory distress syndrome (ARDS). Acute lung injury (ALI) and ARDS are defined by damage to the alveolar epithelium and endothelium, which allows the exudation of protein-rich fluid into the alveolar space. In our preliminary data, we show that vimentin, a type III intermediate filament protein, is required for the activation of the NLRP3 inflammasome. We provide preliminary data that vimentin-/- mice are protected from lung viral pneumonia following infection with influenza A virus (IAV). Increasing evidence from our group and others suggests that these filamentous cytoskeleton structures play key roles in signal transduction pathways and provide a scaffold for the formation and activation of protein complexes, such as the NRLP3 inflammasome. We show that NLRP3 interacts with vimentin and that this protein-protein interaction is required for the processing and maturation of pro-IL- 1¿ into biologically active IL 1¿. Additionally, we provide preliminary data showing that vimentin is required for the interaction and translocation of NOD2 to the outer mitochondrial membrane, which results in the NOD2-mediated activation of IRF3 and release of interferon- from the IAV- infected cells. Based on these preliminary data, we hypothesize that vimentin acts as scaffold for the assembly and activation of the NLRP3 inflammasome and that NOD2 protein interaction with vimentin is required for the activation of IRF3 signaling. We have formulated three interrelated specific aims to study the regulation of vimentin intermediate filaments in both in vivo and in vitro models of influenza A-induced lung injury: Specific Aim 1: To determine the mechanism by which vimentin contributes to activation of NLR proteins during influenza A virus-induced acute lung injury. Specific Aim 2: To define the protein domain(s) in vimentin required for interaction with and activation of the NLRP3 inflammasome. Specific Aim 3: To determine whether the interaction between vimentin and NOD2 is required for the activation of IRF3 and the release of interferon from the IAV-infected cells.

描述（由适用提供）：流感病毒是一种高度传染性的病毒，每年引起上和下呼吸道感染，每年在美国导致200,000次住院和36,000人死亡，并产生重复的发作和大众，并具有可观的归因性发病率和死亡率。与影响力相关的大多数死亡率感染归因于急性呼吸窘迫综合征（ARDS）的发展。急性肺损伤（ALI）和ARDS是通过对肺泡上皮和森林的损害来定义的，这使得富含蛋白质的液体的体验进入肺泡空间。在我们的初步数据中，我们表明Vimentin是III型中间细丝蛋白，需要激活NLRP3炎性体。我们提供了初步数据，即在感染了影响者A病毒（IAV）后，可以保护波形蛋白 - / - 小鼠免受肺病毒性肺炎的保护。我们小组和其他人的越来越多的证据表明，这些丝状细胞骨架结构在信号转导途径中起关键作用，并为蛋白质复合物的形成和激活提供了脚手架，例如NRLP3炎症体。我们表明NLRP3与波形蛋白相互作用，并且这种蛋白质 - 蛋白质相互作用是将pro-il- 1的加工和成熟到生物活性IL中所必需的 1¿。此外，我们提供了初步数据，表明交互需要波形蛋白 NOD2转移到外部线粒体膜上，这导致NOD2介导的IRF3激活并从IAV感染的细胞中释放干扰素。基于这些初步数据，我们假设波形蛋白是NLRP3炎症体组装和激活的支架，并且NOD2蛋白与波形蛋白的相互作用是激活IRF3信号传导所必需的。我们已经制定了三个相互关联的特定目的，以研究在体内和体外和体外模型中对造影症A诱导的肺损伤的调节：特定目的1：确定波形蛋白在造成病毒A诱导的急性肺肺中有助于激活NLR蛋白的机制。特定目标2：定义与NLRP3炎症体相互作用和激活所需的波形蛋白中的蛋白质结构域。特定目标3：确定波形蛋白和NOD2之间的相互作用是否需要激活IRF3和从IAV感染的细胞中释放干扰素。