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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要项目1 严重的病毒性肺炎，由于影响病毒（IAV）损害下呼吸道导致急性呼吸窘迫综合征（ARDS）。 ARDS患者的呼吸衰竭的持续性是持续注射和正常注射机制的失败和肺组织修复。 IAV免疫响应的关键步骤是NLRP3炎症体的激活以及随后的炎症细胞因子IL-1β和IL-18的分泌。波形蛋白调节NLRP3炎性体的形成和激活。我们建议通过在IAV感染的小鼠中暂时删除单核细胞衍生的肺泡巨噬细胞（MOAMS）病毒后清除率中的波形蛋白来调节NLRP3炎症体。莫拉姆斯在免疫响应的主动和延续中起着至关重要的作用，限制了受伤的修复肺组织。我们的数据表明，驱动炎症表型的基因在波形蛋白 - / - 被抑制 moams。在诱导的条件敲除小鼠中使用新型的谱系追踪技术，我们将研究波形蛋白是否通过促进紧随其后的莫拉姆的炎症表型来调节持续的炎症清除IAV。调节性T细胞还通过抑制免疫有助于从病毒肺炎中恢复反应并促进肺组织修复。我们的数据表明，波形蛋白 - / - Treg细胞表现出细胞 - IAV感染后其亲修复功能的自主增加。我们假设有针对性的损失肺泡巨噬细胞和调节性T细胞中的波形蛋白需要促进促进过程严重的IAV感染后。特定目的1。确定单核细胞衍生的牙槽中的靶向损失是靶向损失巨噬细胞抑制其炎症反应并促进严重后的肺修复流感感染。我们建议破坏持续的感染，以限制受伤的肺组织的修复单核细胞衍生的肺泡巨噬细胞在IAV-中暂时控制波形蛋白的缺失。感染的小鼠。具体目的2。确定波形蛋白中间丝的沉积是否原因代谢重编程以抑制肺泡巨噬细胞炎症表型。我们的初步数据表明，从炎症到亲修复巨噬细胞表型的转换与代谢有关波形蛋白中间丝的重编程和沉积。特定目的3。确定临时的，特定于细胞的波形蛋白是否会增强Pro-Repair 从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细胞是否通过增加的细胞自治pro-Repair功能表现出增强腺苷信号传导和两极蛋白产生后，影响了Za病毒感染。