Alveolar type II epithelial cells respond rapidly and in a versatile manner to influenza A Virus infection in vivo and harbor a strong immune-regulatory potential

 

Influenza A virus (IAV) remains a serious health burden and risk for the human population. Next to severe respiratory infections, patients are at risk for bacterial pneumonia due to virally induced immune modulation. In the lower lung, type II alveolar epithelial cells (AECII) are being increasingly recognized for their immunological potential and at the same time display the primary targets for IAV replication. In order to increase our understanding of early anti-IAV immune responses and the role of AECII in these in vivo, we characterized the AECII response during early IAV infection in a mouse infection model. To this end we sorted AECII from the lungs of infected mice and analyzed their gene expression profile through microarray analyses, which revealed a rapid and extensive regulation of gene expression. The comparison of AECII transcriptional regulation to that in lung tissue revealed a strong contribution of AECII to the overall lung anti-IAV response. The expression of a plethora of antiviral factors, cytokines and chemokines, altogether with a high prevalence of interferon-stimulated genes, was induced and correlated to type I interferon production and the recruitment of immune cells to the respiratory tract. To assess the immune-regulatory potential of AECII with regard to secondary bacterial infections, we analyzed effects of the AECII anti-viral response on alveolar macrophages. To this end the murine AECII cell line MLE-15 was treated with the Toll-like receptor 3 ligand poly(I : C) or inactivated IAV and the effect of AECII-secreted factors on alveolar macrophage phagocytic function, which is key to the defense against respiratory bacterial infections, was analyzed. Indeed, AECII-conditioned medium following treatment significantly inhibited the phagocytic function of primary alveolar macrophages. Taken together, these studies demonstrate the strong immunological potential of AECII and have implications for our understanding of respiratory epithelial cell biology, the early induction of anti-IAV responses and the mechanisms underlying enhanced susceptibility to secondary bacterial infections following IAV infection.