Interferon lambda restricts herpes simplex virus skin disease by suppressing neutrophil-mediated pathology

Abstract

Type III interferons (IFN-{lambda}) are antiviral and immunomodulatory cytokines that have been best characterized in respiratory and gastrointestinal infections, but the effects of IFN-{lambda} against skin infections have not been extensively investigated. We sought to define the skin-specific effects of IFN-{lambda} against the highly prevalent human pathogen herpes simplex virus (HSV). We infected mice lacking the IFN-{lambda} receptor (Ifnlr1-/-), both the IFN-{lambda} and the IFN-{beta} receptor (Ifnar1-/- Ifnlr1-/-), or IFN-{lambda} cytokines (Ifnl2/3-/-) and found that IFN-{lambda} 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-{lambda} signaling in both keratinocytes and neutrophils was necessary to control HSV-1 skin lesion severity, and that IFN-{lambda} signaling in keratinocytes suppressed CXCL9-mediated neutrophil recruitment to the skin. Furthermore, depleting neutrophils or blocking CXCL9 protected against severe HSV-1 skin lesions in Ifnlr1-/- mice. Altogether, our results suggest that IFN-{lambda} plays an immunomodulatory role in the skin that restricts neutrophil-mediated pathology during HSV infection, and suggest potential applications for IFN-{lambda} in treating viral skin infections. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/557277v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@110a7feorg.highwire.dtl.DTLVardef@853e46org.highwire.dtl.DTLVardef@1bb744aorg.highwire.dtl.DTLVardef@1cfdf94_HPS_FORMAT_FIGEXP M_FIG C_FIG