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

项目总结项目1 重症病毒性肺炎，因甲型流感病毒(IAV)损害下呼吸道而引起急性 呼吸窘迫综合征(ARDS)。ARDS患者呼吸衰竭的持续性是一种 持续性炎症的后果和正常的炎症消退机制和 肺组织修复。IAV免疫应答的关键步骤是激活NLRP3炎症体 随后分泌炎性细胞因子IL-1β和IL-18。 波形蛋白调节NLRP3炎症体的形成和激活。我们建议通过暂时删除IAV感染小鼠病毒清除后单核细胞来源的肺泡巨噬细胞(MoAM)中的波形蛋白来调节NLRP3炎症体。 巨噬细胞巨噬细胞在免疫反应的启动和持续过程中起着关键作用，限制了损伤的修复。 肺组织。我们的数据显示，在Vimentin−/−中，驱动炎症表型的基因被抑制 动画片。在可诱导的条件性基因敲除小鼠中使用新的血统追踪技术，我们将研究 波形蛋白是否通过促进以下炎症表型而调节持续性炎症 放行室内空气调节器。调节性T细胞还通过抑制免疫有助于病毒性肺炎的康复 促进肺组织修复。我们的数据表明，Vimentin−/−Treg细胞表现出一种细胞- 在IAV感染后，它们的修复功能自主增加。我们假设定向损失 肺泡巨噬细胞和调节性T细胞中波形蛋白的表达是促进修复过程所必需的 在严重的IAV感染之后。 具体目的1.确定单核细胞来源的肺泡中波形蛋白的靶向性丢失 巨噬细胞抑制炎症反应并促进重症肺损伤后的修复 流感感染。我们建议通过以下方法来破坏限制受损肺组织修复的持续性炎症 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缺失 受感染的小鼠。 具体目的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。我们的预赛 数据表明，巨噬细胞表型从炎症性向修复前期的转变与代谢有关。 波形蛋白中间丝的重新编程和解聚。 具体目标3.确定暂时的、细胞特异性的波形蛋白丢失是否增强了促修复 调节性T细胞在IAV肺炎康复过程中的作用我们建议确定 Vimentin−/−Treg细胞是否通过增加 甲型流感病毒感染后腺苷信号转导和双调节素的产生。

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.