Fibroblast growth factor-9 expression in airway epithelial cells amplifies the type I interferon response and alters influenza A virus pathogenesis

Abstract

Influenza A virus (IAV) preferentially infects conducting airway and alveolar epithelial cells in the lung. The outcome of these infections is impacted by the host response, including the production of various cytokines, chemokines, and growth factors. 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. We therefore hypothesized that FGF9 would protect the lungs from respiratory virus infection and evaluated IAV pathogenesis in mice that overexpress FGF9 in club cells in the conducting airway epithelium (FGF9-OE mice). However, we found that FGF9-OE mice were highly susceptible to IAV and Sendai virus infection compared to control mice. FGF9-OE mice displayed elevated and persistent viral loads, increased expression of cytokines and chemokines, and increased numbers of infiltrating immune cells as early as 1 day post-infection (dpi). Gene expression analysis showed an elevated type I interferon (IFN) signature in the conducting airway epithelium and analysis of IAV tropism uncovered a dramatic shift in infection from the conducting airway epithelium to the alveolar epithelium in FGF9-OE lungs. These results demonstrate that FGF9 signaling primes the conducting airway epithelium to rapidly induce a localized, protective IFN and proinflammatory cytokine response during viral infection. Although this response protects the airway epithelial cells from IAV infection, it allows for early and enhanced infection of the alveolar epithelium, ultimately leading to increased morbidity and mortality. Our study illuminates a novel role for FGF9 in regulating respiratory virus infection and pathogenesis. Author SummaryInfluenza viruses are respiratory viruses that cause significant morbidity and mortality worldwide. In the lungs, influenza A virus primarily infects epithelial cells that line the conducting airways and alveoli. Fibroblast growth factor-9 (FGF9) is a growth factor that has been shown to have antiviral activity and is upregulated during early IAV infection in asymptomatic patients, leading us to hypothesize that FGF9 would protect the lung epithelium from IAV infection. However, mice that express and secrete FGF9 from club cells in the conducting airway had more severe respiratory virus infection and a hyperactive inflammatory immune response as early as 1 day post-infection. Analysis of the FGF9-expressing airway epithelial cells found an elevated antiviral and inflammatory interferon signature, which protected these cells from severe IAV infection. However, heightened infection of alveolar cells resulted in excessive inflammation in the alveoli, resulting in more severe disease and death. Our study identifies a novel antiviral and inflammatory role for FGFs in the lung airway epithelium and confirms that early and robust IAV infection of alveolar cells results in more severe disease.