Project 1: Vimentin regulates host response and repair mechanisms to influenza A viral pneumonia

项目1：波形蛋白调节宿主对甲型流感病毒性肺炎的反应和修复机制

• 批准号: 10696962
• 负责人: KAREN M RIDGE
• 金额: $ 51.66万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10696962
• 关键词: 2019-nCoV; Acute; Acute Respiratory Distress Syndrome; Adenosine; Alveolar Macrophages; Amphiregulin; Antibodies; Automobile Driving; COVID-19; COVID-19 patient; COVID-19 pneumonia; Cells; Clinical; Credentialing; Data; Epidermal Growth Factor; Epithelium; Etiology; Exhibits; Failure; Flow Cytometry; Funding; Funding Opportunities; Gene Expression; Gene Expression Profile; Genes; IL18 gene; Immune response; Impairment; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Influenza A virus; Instruction; Interleukin-1 beta; Intermediate Filaments; Knockout Mice; Lower respiratory tract structure; Lung; Macrophage; Mediating; Metabolic; Monoclonal Antibodies; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; Outcome; Patients; Phenotype; Play; Pneumonia; Process; Production; Proliferating; Pulmonary Inflammation; Recovery; Regulatory T-Lymphocyte; Reporting; Research; Resolution; Respiratory Failure; Role; Signal Transduction; Structure of parenchyma of lung; Techniques; Testing; Tissues; Vimentin; Viral; Viral Pneumonia; Virus; Virus Diseases; chemokine; clinically relevant; community acquired pneumonia; conditional knockout; cytokine; depolymerization; experimental study; extracellular; improved; influenza infection; injury and repair; lung injury; lung repair; monocyte; mortality; mouse model; novel; participant enrollment; pathogen; placebo controlled trial; prevent; recruit; repair function; repaired; targeted treatment; tissue repair

PROJECT SUMMARY PROJECT 1 Severe viral pneumonia, due to influenza A virus (IAV) damages the lower respiratory tract to cause acute respiratory distress syndrome (ARDS). The persistence of respiratory failure in patients with ARDS is a consequence of persistent inflammation and the failure of normal mechanisms of inflammation resolution and lung tissue repair. A crucial step in the immune response to IAV is the activation of the NLRP3 inflammasome and subsequent secretion of inflammatory cytokines, IL-1β and IL-18. Vimentin regulates the formation and activation of the NLRP3 inflammasome. We propose to modulate the NLRP3 inflammasome by temporally deleting vimentin in monocyte-derived alveolar macrophages (MoAMs) post-viral clearance in IAV-infected mice. MoAMs play crucial roles in both initiation and continuation of the immune response, limiting repair of the injured lung tissue. Our data revealed that genes driving the inflammatory phenotype are suppressed in Vimentin−/− MoAMs. Using novel lineage-tracing techniques in inducible conditional knockout mice, we will investigate whether vimentin regulates persistent inflammation by promoting an inflammatory phenotype in MoAMs following clearance of IAV. Regulatory T cells also contribute to recovery from viral pneumonia by suppressing immune responses and promoting lung tissue repair. Our data suggest that Vimentin−/− Treg cells exhibit a cell- autonomous increase in their pro-repair function following IAV infection. We hypothesize that a targeted loss of vimentin in alveolar macrophages and regulatory T cells is required to promote pro-repair processes following severe IAV infection. Specific Aim 1. To determine whether a targeted loss of vimentin in monocyte-derived alveolar macrophages suppresses their inflammatory response and promotes lung repair following severe influenza infection. We propose to disrupt the persistent inflammation that limits repair of injured lung tissue by temporally-controlled deletion of vimentin in monocyte-derived alveolar macrophages post-viral clearance in IAV- infected mice. Specific Aim 2. To determine whether depolymerization of vimentin intermediate filaments causes metabolic reprogramming to suppress alveolar macrophage inflammatory phenotype. Our preliminary data suggest that a switch from inflammatory to pro-repair macrophage phenotype is associated with metabolic reprogramming and depolymerization of vimentin intermediate filaments. Specific Aim 3. To determine whether temporal, cell-specific loss of vimentin augments the pro-repair function of regulatory T cells during recovery from IAV-induced pneumonia. We propose to determine whether Vimentin−/− Treg cells exhibit their augmented cell-autonomous pro-repair function via increased adenosine signaling and amphiregulin production following influenza A virus infection.

项目概要 项目 1 严重病毒性肺炎，由于甲型流感病毒（IAV）损害下呼吸道引起急性 呼吸窘迫综合征（ARDS）。 ARDS 患者持续出现呼吸衰竭是一个重要因素 持续炎症和正常炎症消退机制失败的结果 肺组织修复。 IAV 免疫反应的关键一步是 NLRP3 炎性体的激活 以及随后分泌炎症细胞因子 IL-1β 和 IL-18。 波形蛋白调节 NLRP3 炎症小体的形成和激活。我们建议通过在 IAV 感染小鼠病毒清除后暂时删除单核细胞来源的肺泡巨噬细胞 (MoAM) 中的波形蛋白来调节 NLRP3 炎症小体。 MoAM 在免疫反应的启动和持续中发挥着至关重要的作用，限制了损伤的修复 肺组织。我们的数据显示，驱动炎症表型的基因在波形蛋白中受到抑制−/− MoAM。在诱导条件敲除小鼠中使用新颖的谱系追踪技术，我们将研究 波形蛋白是否通过促进 MoAM 中的炎症表型来调节持续性炎症 IAV 的许可。调节性 T 细胞还可以通过抑制免疫来促进病毒性肺炎的恢复 反应并促进肺组织修复。我们的数据表明 Vimentin−/− Treg 细胞表现出细胞- IAV 感染后其促修复功能自主增强。我们假设目标损失 肺泡巨噬细胞和调节性 T 细胞中的波形蛋白是促进修复过程所必需的 严重 IAV 感染后。 具体目标 1. 确定单核细胞来源的肺泡中波形蛋白是否有针对性的丢失 巨噬细胞抑制炎症反应并促进严重肺损伤后的肺部修复 流感感染。我们建议通过以下方式破坏限制受损肺组织修复的持续炎症： IAV-病毒清除后单核细胞来源的肺泡巨噬细胞中波形蛋白的时间控制删除 被感染的老鼠。 具体目标 2. 确定波形蛋白中间丝的解聚是否会导致 代谢重编程抑制肺泡巨噬细胞炎症表型。我们的初步 数据表明，从炎症巨噬细胞表型转变为促修复巨噬细胞表型与代谢相关 波形蛋白中间丝的重编程和解聚。 具体目标 3. 确定波形蛋白的时间性、细胞特异性损失是否会增强促修复 IAV 诱导的肺炎恢复过程中调节性 T 细胞的功能。我们建议确定 波形蛋白−/− Treg 细胞是否通过增加 甲型流感病毒感染后腺苷信号传导和双调蛋白产生。