Abstract
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 have 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 interferon beta (IFNβ) release into the airways was significantly enhanced in epTGFβKO mice compared with control mice, with elevated IFNβ on day 1 in epTGFβKO compared with control mice. This induced a heighted antiviral 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 microenvironmental niche in shaping initial immune responses to viral infection and controlling host disease.
Highlights
Pulmonary epithelial cells are continually exposed to an inhaled environment comprising billions of innocuous particles as well as potential pathogens
Epithelial tumor growth factor (TGF)-b promotes influenza-induced pathology Mice lacking expression of TGF-b1 in club cells that comprise 80% of bronchiolar epithelial cells were generated by crossing TGF-b1fl/fl mice with CCSP Tet-on CRE mice (Figure 1a).[3]
Control mice showed characteristic weight loss associated with influenza infection, we found that epTGFbKO mice were strongly protected from weight loss (Figure 1b), and showed only a minimal weight change from mock-infected mice on day 3 post infection. epTGFbKO mice were protected from pathological changes within lung tissue induced by influenza infection (Figure 1c,d)
Summary
Pulmonary epithelial cells are continually exposed to an inhaled environment comprising billions of innocuous particles as well as potential pathogens. Seasonal infections with the respiratory virus influenza A result in significant mortality and morbidity in vulnerable groups as well as substantial healthcare and economic costs in the healthy population.[4] Epithelial cells sense infection by pathogens via recognition of pathogenassociated molecular patterns and damage-associated molecular pattern molecules. Activation of these pathways induces rapid release of epithelial-derived type I (interferon alpha and beta (IFNa and IFNb, respectively)) and type III IFNs (IFNl), which are vital for antiviral immunity
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