Patients with acute lung injury and acute respiratory distress syndrome (ARDS) have impaired gas exchange due to altered alveolar epithelial function, which results in accumulation of edema fluid leading to alveolar damage. Seasonal influenza infection affects a significant proportion of the population in the United States and worldwide, and while most patients infected with influenza A recover, in some patients influenza virus infection may cause severe pneumonitis, ARDS and death. Alveolar epithelial cells are targets for influenza virus A, and play an important role in mounting the initial host response. Upon influenza A virus infection, alveolar epithelial cells release cytokines that contribute to th recruitment of monocytes and macrophages to the site of infection and also participate in viral clearance, which may limit the infection from spreading. However, the underlying mechanisms of these events are not completely understood. We hypothesize that in addition to its barrier function, the alveolar epithelium plays an important effector role in protecting the lung from severe injury. The first aim of this grant proposal seeks assess whether IAV-mediated increases in LUBAC expression during infection contributes to dysregulated cytokine production leading to acute lung injury. The second specific aim will determine whether linear ubiquitination of NEMO is necessary for robust NF-?B activation seen in IAV pneumonitis and in studies proposed for the third specific aim we propose to determine whether deletion of the LUBAC component HOIL-1L, exclusively in the lung epithelium of mice, will decrease the IAV induced lung injury and improve survival. Understanding the mechanism(s) that lead to alveolar epithelial driven cytokine storm during influenza virus infection will provide novel information that is of clinical relevance and has the potential for innovative approaches in the treatment of patients with acute lung injury.