An Epithelial Integrin Regulates the Amplitude of Protective Lung Interferon Responses against Multiple Respiratory Pathogens

Meliopoulos, Victoria A.; Van de Velde, Lee-Ann; Van de Velde, Nicholas C.; Karlsson, Erik A.; Neale, Geoff; Vogel, Peter; Guy, Cliff; Sharma, Shalini; Duan, Susu; Surman, Sherri L.; Jones, Bart G.; Johnson, Michael D. L.; Bosio, Catharine; Jolly, Lisa; Jenkins, R. Gisli; Hurwitz, Julia L.; Rosch, Jason W.; Sheppard, Dean; Thomas, Paul G.; Murray, Peter J.; Schultz-Cherry, Stacey

Given the role of the β6 integrin in modulating ALI, we hypothesized that its upregulation during respiratory infections such as influenza would be important for viral pathogenesis. To test this, β6 KO mice were infected with the 2009 pandemic H1N1 influenza virus. β6-deficient mice were protected from influenza virus-induced disease as well as a broad range of respiratory pathogens, in most cases independent of effects on overall microbial numbers. Mechanistically, we found that epithelial β6 controls the homeostatic lung interferon response. In the absence of β6, type I interferon signaling is constitutive, causing the host to have an advantage over the spread of the virus. This protective phenotype was reversed by exogenous TGF-β1 or elimination of the type I interferon receptor, suggesting that αVβ6 controls a communication system between lung epithelia and immune cells through a TGF-β-dependent mechanism. These studies have important implications as transient inhibition of αVβ6 may represent a potential therapy for the management of acute lung injury.