Research Project
10269674
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-1? 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.
