ER Stress Disrupts the Airway Epithelium and Reduces Host Defense during Influenza A Virus Infection

Secondary Streptococcus pneumoniae (Spn) infection to influenza A virus (IAV) frequently leads to an increase in morbidity and mortality of IAV. Our recent work establishes that IAV infection disrupts bacterial host defense in the lung epithelium through loss of cystic fibrosis transmembrane conductance regulator protein (CFTR) function, causing an acidification of the ASL and subsequently increasing susceptibility to Spn. Infection with IAV and other respiratory pathogens cause a robust endoplasmic reticulum (ER) stress response. However, the role of this acute ER stress response in predisposing the airway epithelium to susceptibility to bacterial infections remains unknown. Utilizing a primary differentiated human bronchial airway epithelial cell (HBEC) culture system, we find that both IAV-induced ER stress and ER stress alone increase susceptibility to Spn in the airway epithelium and lead to a loss of CFTR activity, subsequently causing a disruption in the rheostatic properties of the airway surface liquid. Importantly, in HBECs without functional CFTR, modulation of ER stress in the presence and absence IAV of has no effect on susceptibility to Spn. Restoration of ASL pH after ER stress in HBECs with functional CFTR reduces Spn, suggesting that ER stress increases susceptibility to bacterial infection by disrupting CFTR and causing an acidification of the ASL. Here, we demonstrate a clear role for ER stress in disruption of both the airway epithelium and bacterial host defense mechanisms during respiratory viral infection.