Project 2: Role of vimentin in influenza A lung injury
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. Infection with influenza A virus can result in the development of acute respiratory distress syndrome (ARDS). Acute lung injury (ALI) and ARDS often manifest as part of an inflammatory process resulting in the development of diffuse alveolar damage, capillary injury, and exudation of protein-rich fluid into the alveolar space. We will test the hypothesis that vimentin is required for the activation of the NLRP3 inflammasome, which leads to the development of lung viral pneumonia. We provide preliminary data that vimentin−/− mice are protected from lung viral pneumonia following infection with influenza A virus. Increasing evidence from the field of intermediate filament biology and our group 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 in the cell, 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-1β into biologically active IL-1β. Additionally, we provide preliminary data 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 interferon in IAV infected cells. We hypothesis 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 lung vial pneumonia: Specific Aim 1: To determine the mechanism by which vimentin, a type III intermediate filaments protein, 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 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 interferon in IAV infected cells.
Faculty Associated With Project 2
Karen Ridge, Project Leader
Robert Goldman, Co-Investigator
Christian Stehlik, Co-Investigator