Abstract Type A influenza virus (IAV) is a major human pathogen with the capacity to rapidly spread worldwide and to produce severe and sometimes fatal lung infections characterized by severe pneumonia. Disease severity resulting from IAV infection reflects the extent of virus replication in cells of the respiratory tract and the strength or magnitude of the host innate and adaptive immune response. Thus, the host immune response is not only responsible for IAV clearance but also contributes to tissue injury during infection. However, while the role of immune cells in virus elimination is well documented, the role of immune cells and in particular innate immune cells in regulating the susceptibility of respiratory tract cells in vivo to IAV infection is only poorly understood. We recently reported in a novel mouse model of IAV infection that upregulation of the cysteinyl leukotriene (5-lipoxygenase) metabolic pathway in terminal airway (alveolar) epithelial cells is associated with enhanced susceptibility of these cells to IAV infection. Furthermore, terminal airway resident (alveolar) macrophages suppress the upregulation of the 5-lipoxygenase pathway in terminal airway epithelial cells and as a consequence reduce the susceptibility of the cells to IAV infection. The program described in this application is designed to explore the role of the 5-lipoxygenase metabolic pathway and signaling via cysteinyl leukotriene receptors in controlling the susceptibility of airway epithelial cells to IAV infection and the mechanism by which terminal airway macrophages reduce susceptibility. We will establish the requirement for 5-lipoxygenase pathway enzymatic activity, cysteinyl leukotriene receptor signaling in terminal airway epithelial cells and explore the mechanism by which signaling through this receptor enhances susceptibility to IAV infection (Aim 1). In conjunction, we will explore the interaction between terminal airway macrophages, airway epithelial cells and IAV resulting in suppression of susceptibility of airway epithelial cells to infection, the mechanism of macrophage action leading to suppression and extend this analysis into the human (Aim 2).