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

Overall, loss of the β6 integrin resulted in protection from a variety of respiratory infections including influenza and Sendai viruses, bacterial pneumonia, and viral-bacterial co-infections. β6 KO mice had significantly reduced extent and severity of lung injury and inflammation, reduced collagen deposition despite no difference in viral titer, consistent with studies using β6 integrin function blocking antibodies [57] , with virus infection being more restricted to airways instead of infiltrating the deep-lung alveolar spaces. β6 function blocking antibodies have been successfully used to improve outcome in idiopathic pulmonary fibrosis and currently recruiting for phase II human clinical trials [58, 59] . While the β6 integrin represents an attractive therapeutic target to combat pulmonary disease, it does play a role in lung homeostasis. While transient inhibition of β6 in the lung results in resistance to infection, complete lack of β6 function for long periods of time could be detrimental. Over long periods of time, β6 KO mice over produce macrophage-derived matrix metalloprotease MMP12, leading to emphysema and destruction of pulmonary tissue [16] . However, for short-term protection against the adverse consequences of potentially lethal pulmonary viral infections, our work identifies the αVβ6 integrin as a potentially attractive therapeutic target for transient intervention in lung viral infection. Mice C57BL/6, Ifnb1-YFP, CCR2 KO and CD45.1 mice were obtained from Jackson Laboratories (Bar Harbor, ME). Itgb6 -/mice, generated as described [9] and backcrossed 10 generations onto the C57BL/6 background, were obtained from Dean Sheppard (UCSF) then bred at St Jude Children's Research Hospital. Littermate controls from heterozygous crosses were used as controls. IFNAR KO mice were obtained from Dr. Laura Knoll (University of Wisconsin). Knockouts were confirmed by PCR using primer sets (CCR2, IFNAR) reported on the Jackson Laboratories website, or as previously described (β6) [16] .