Epithelial derived TGF-β1 acts as a pro-viral factor in the lung during influenza A infection

Mucosal surfaces are under constant bombardment from potentially antigenic particles and so must maintain a balance between homeostasis and inappropriate immune activation and consequent pathology. Epithelial cells play a vital role orchestrating pulmonary homeostasis and defense against pathogens. TGF-β regulates an array of immune responses- both inflammatory and regulatory, however its function is highly location and context dependent. We demonstrate that epithelial derived TGF-β acts as a pro-viral factor suppressing early immune responses during influenza A infection. Mice specifically lacking bronchial epithelial TGF-β1 (epTGFβKO) displayed marked protection from influenza induced weight loss, airway inflammation and pathology. However, protection from influenza induced pathology was not associated with a heightened lymphocytic immune response. In contrast, the kinetics of IFNβ release into the airways was significantly enhanced in epTGFβKO mice compared to control mice, with elevated IFNβ at day 1 in epTGFβKO compared to control mice. This induced a heighted anti-viral state resulting in impaired viral replication in epTGFβKO mice. Thus, epithelial derived TGF-β acts to suppress early IFNβ responses leading to increased viral burden and pathology. This study demonstrates the importance of the local epithelial micro-environmental niche in shaping initial immune responses to viral infection and controlling host disease.