Interferon signal transduction in airway barrier epithelial cells is key to controlling human picornavirus infection in the lung

Abstract

Abstract Interferon (IFN) signal transduction is required for defense against viral infection, and this signal in airway barrier epithelial cells is assumed to be responsible for controlling common respiratory viruses. However, these conventional concepts have not been rigorously tested in an experimental model given the relative lack of native human respiratory viruses that replicate efficiently in non-human models and the absence of tools to analyze IFN signal transduction specific to airway epithelial cells. To address these issues, we generated a new line of Scgb1a1-Foxj1-Cre-Stat1f/f mice to selectively target IFN signaling in airway epithelial cells and tested these mice for control of infection with the human picornavirus pathogen EV-D68 that might cause more severe infection than human rhinoviruses. Our results show significant replication of EV-D68 with a 1×105-fold increase in viral RNA in lungs of Scgb1a1-Foxj1-Cre-Stat1f/f mice compared to wild-type mice and was similar to viral titer and accompanying lung inflammation and mucous cell formation in conventional Stat1−/− mice. We also found increases in viral titer and inflammation in Scgb1a1-Foxj1-Cre-Stat1f/f mice compared to wild-type mice after the natural mouse pathogen murine parainfluenza virus aka Sendai virus (SeV) infection, but in this case the defect was significantly more pronounced in Stat1−/− mice, consistent with evidence of extra-airway spread of SeV infection. Together, these results indicate a critical requirement for airway epithelial cell capacity for IFN signaling in protection against respiratory picornavirus infection, and to our knowledge, the best evidence to date for the proposed role of airway barrier epithelial cells in host defense.