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

β6 KO mice are protected from diverse respiratory infections β6 expression is induced upon mechanical or inflammatory injury and is an important mediator of ALI [10, 12, 14, 30] . Thus, we hypothesized that upregulation of the β6 integrin during respiratory infections would be involved in viral pathogenesis. To test this, we measured β6 expression by quantitative RT-PCR at different times post-influenza infection. Consistent with lung injury models, β6 mRNA was significantly upregulated in whole lung homogenates by 3 days post-infection (dpi) and expression remained elevated through 5 dpi (p < 0.0001) correlating with the appearance of ALI (Fig 1A) . We then intranasally infected WT and Itgb6-deficient mice (β6 KO mice) with A/California/04/2009 (CA/09) H1N1 virus and monitored morbidity for 12 dpi. Compared to WT controls, β6 KO mice lost significantly less weight (4, 6, and 8 dpi p < 0.0001) and began to recover by 10 dpi, while WT mice lost weight and either succumbed to infection or were euthanized due to morbidity between 6-10 dpi (Fig 1B and 1C ). The dose of CA/09 virus used (10 4 TCID 50 ) was lethal to all WT mice, while 70% β6 KO mice survived the infection (p = 0.0090). Mouse lethal dose 50 (MLD 50 ) studies demonstrated the resistance of the β6 KO to influenza infection, with WT mice having an MLD 50 of 10 2.5 versus 10 5.3 for the KO to the CA/09 virus. Protection was not limited to H1N1 infection; β6 KO mice were also protected from an emerging strain of avian influenza virus associated with severe and even fatal human respiratory disease [17] , A/Anhui/1/2013 (H7N9) influenza virus (p = 0.0326, Fig 1D) . β6 KO mice were also significantly protected from a lethal challenge of Sendai virus (p = 0.006, Fig 1E) and Streptococcus pneumonia (p = 0.0082, Fig 1F) .