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).
Type A influenza viruses a major human pathogen with the capacity to produce both epidemic disease (seasonal infections) as well as pandemic disease resulting from infections on worldwide scale with the potential for morbidity and mortality among infected patients measurable in the millions. The worldwide outbreak in 2009 of the novel H1N1 swine like influenza virus infection in the human population highlights the speed with which this virus can spread. One of the most serious consequences of influenza infection is the development of a primary influenza pneumonia. Although infrequent, primary influenza pneumonia has a very high morbidity and mortality rate ? anywhere between 10% to 30% mortality of patients with pneumonia. Pneumonia is caused when the virus infects cells deep in the lungs where oxygen exchange occurs. When a large percentage of these terminal airway cells are infected, this results in the respiratory compromise associated with pneumonia. We have discovered that infection of these terminal airway cells can be suppressed by employing a technique based on how another cell type deep in the lungs, alveolar macrophages, prevent infection of these terminal airway epithelial cells. In a mouse model of influenza infection we have found that similar to the action of alveolar macrophages, we can limit the extent of influenza infection of the terminal airway cells by administering a class of drugs typically use in the treatment of asthma called leukotriene receptor antagonists ? specifically Accolade and Singulair. Our results raise the possibility that individuals infected with influenza can take this class of drugs to prevent the development of influenza pneumonia. I propose research explores the mechanism by which such drugs can prevent the development of severe influence infection both in the mouse and in human studies in the test tube.
