Date of Award

Spring 5-15-2022

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Microbiology & Microbial Pathogenesis)

Degree Name

Doctor of Philosophy (PhD)

Degree Type



Influenza A virus (IAV) is a respiratory virus in the Orthomyxoviridae family which causes both seasonal epidemics and pandemics. IAV preferentially infects epithelial cells in the upper and lower respiratory tract, resulting in a range of disease severity from mild upper respiratory infections to potentially-lethal pneumonia. Ultimately, the severity of symptoms and complications from IAV infection depends on control of virus replication in the lungs, the inflammatory nature of the immune response, and the effectiveness of post-infection lung repair to regain pulmonary function. An arsenal of secreted proteins in the lung regulates these antiviral, inflammatory, and regenerative activities during infection, including interferons (IFNs) and other cytokines, chemokines, and growth factors. Fibroblast growth factors (FGFs) are a family of signaling proteins that are crucial for tissue development and maintenance and, in recent years, FGFs in particular have become appreciated for their myriad and pleiotropic roles in promoting or suppressing viral infection. Fibroblast Growth Factor-9 (FGF9) is required for lung development, can display antiviral activity in vitro, and is upregulated in asymptomatic patients during early IAV infection. Therefore, we evaluated FGF9’s ability to regulate respiratory virus infection and interrogated IAV pathogenesis in mice that overexpress FGF9 in club cells in the conducting airway epithelium (FGF9-OE mice). In my thesis work, we found that FGF9-OE mice were highly susceptible to IAV infection and displayed persistent IAV titers compared to control mice. As early as 1 day post-infection (dpi), FGF9-OE mice displayed elevated expression of cytokines and chemokines in the lung and increased numbers of infiltrating innate immune cells. Gene expression analysis in the airway epithelial cells revealed an elevated type I IFN signature in the airways of FGF9-OE mice at 1 day post-infection, including a significant upregulation of antiviral IFN-stimulated genes. However, these changes were driven by viral infection, since FGF9 overexpression alone resulted in a limited increase in cytokines, chemokines, or ISG expression. In an effort to determine how this IFN signature in airway epithelial cells impacted IAV tropism, we uncovered a dramatic shift in infection from the conducting airway epithelium to the alveolar epithelium in FGF9-OE lungs at 1 dpi, in addition to persistent alveolar infection at 6 dpi in areas of significant alveolitis. These results demonstrate that FGF9 signaling primes the conducting airway epithelium to rapidly induce a localized, protective IFN response during viral infection but simultaneously allows for early and enhanced infection of the alveolar epithelium, ultimately leading to increased alveolar inflammation and more severe disease. Collectively, our studies illuminate a novel role for FGF9 in regulating respiratory virus infection and the quality of the lung’s immune response to infection. Furthermore, the development of this model and utilization in infection studies will serve as the impetus for future research, including how FGF9 may regulate IFN signaling in certain cell types, the regulation of inflammatory immune responses during respiratory virus infection, and FGF9’s potential impact on post-infection lung repair.


English (en)

Chair and Committee

Deborah J. Lenschow

Committee Members

Christina L. Stallings

Included in

Virology Commons