RNA sequencing of sorted conducting airway epithelial cells from FGF9-overexpressing and control mouse lungs at 1 day post-infection with IAV

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.