Molecular Mechanisms of Damage to the Alveolar Microenvironment During Influenza A Infection

Abstract

Since influenza A virus (IAV) was first isolated in the early 1930s, it has become one of the most well studied viruses in the history of science. However, there is still much to be learned about how IAV infection disrupts the alveolar microenvironment at the molecular level and how these changes perpetuate injury to the human host. This dissertation presents findings that address some of the current gaps in knowledge pertaining to the molecular pathophysiology of influenza-associated severe illness. It centers on the concept that lung injury from IAV is not just a result of direct viral damage to lung epithelial cells but is also propagated by secondary changes in alveolar-capillary barrier permeability and subsequent lung inflammation that occur during infection. I present data focusing on two pathophysiological effects of severe IAV infection with acute lung injury: 1) cleavage of the alveolar epithelial glycocalyx and 2) propagation of inflammation due to release of cell free hemoglobin (CFH) into the airspace. I show that matrix metalloproteinases (MMPs) are the enzyme class responsible for IAV-associated glycocalyx shedding and that modulation of MMPs and glycocalyx shedding affects viral dynamics and alveolar epithelial injury. I also show that airspace inflammation due to CFH is mediated by toll-like receptor 4 signaling on macrophages. Taken together, my data indicate that the secondary effects of IAV infection like glycocalyx shedding and CFH-associated inflammation are significant sources of lung injury during IAV and have important molecular signaling signatures.