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

To determine if the increased type I IFN signaling in β6 KO mice was responsible for the enhanced protection, we crossed β6 KO with Ifnar -/mice (β6/IFNAR double KO), which lack the type I IFN receptor and all type I IFN signaling, then challenged these mice and their cognate controls created from the same heterozygote crosses with 10 4 TCID 50 of CA/09 virus. Mice were monitored for morbidity and mortality for 12 days. β6/IFNAR double KO mice did not survive infection (p = 0.0039 compared to β6 KO, Fig 9A) and exhibited similar mortality to WT mice. Further, imaging WT, β6 KO, IFNAR KO, and β6/IFNAR double KO mice infected with CA/09-NLuc reporter virus at 3 and 7 dpi showed that the ββ6 KO mice had reduced viral spread in the lungs as compared to WT controls (S1A and S1B Fig). In contrast, However, the 'activated' CD11c + CD11b + macrophage phenotype of the β6 KO crosses remained the same as β6/IFNAR double KO (Fig 9B) suggesting the protective anti-viral phenotype of the β6 KO is type I IFNAR-dependent, but another pathway regulates the phenotype of the resident macrophages in the β6 KO independent of type I IFNs.