IFN-? signaling protects mice from severe HSV-1 skin disease II
Type III interferons (IFN-?) are antiviral and immunomodulatory cytokines that have been best characterized in respiratory and gastrointestinal infections, but the effects of IFN-? against skin infections have not been extensively investigated. We sought to define the skin-specific effects of IFN-? against the highly prevalent human pathogen herpes simplex virus (HSV). We infected mice lacking the IFN-? receptor (Ifnlr1-/-), both the IFN-? and the IFN-aß receptor (Ifnar1-/- Ifnlr1-/-), or IFN-? cytokines (Ifnl2/3-/-) and found that IFN-? restricts the severity of HSV-1 and HSV-2 skin lesions, independent of a direct effect on viral load. Using conditional knockout mice, we found that IFN-? signaling in both keratinocytes and neutrophils was necessary to control HSV-1 skin lesion severity, and that IFN-? signaling in keratinocytes suppressed CXCL9-mediated neutrophil recruitment to the skin. Furthermore, depleting neutrophils prevented the development of severe HSV-1 skin lesions in Ifnlr1-/- mice. Altogether, our results suggest that IFN-? plays an immunomodulatory role in the skin that restricts neutrophil-mediated pathology during HSV infection, and suggest potential applications for IFN-? in treating viral skin infections. Overall design: To uncover the role for IFN-? signaling in epithelial cells in protecting mice from severe HSV-1 skin disease. To differentiate effects that were specific to IFN-?, and not necessarily dependent on shared canonical signaling with IFN-ß, we treated A549s (RenLuc, IFNLR1, and IFNAR1) with both IFNs or media alone for 8 hours and defined differentially expressed genes.