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bioRxiv · 10.1101/2023.09.11.557277

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

Philip, D. T.·Goins, N. M.·Catanzaro, N. J.·Misumi, I.·Whitmire, J. K.·Atkins, H. M.·Lazear, H. M.
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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

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Philip, D. T., Goins, N. M., Catanzaro, N. J., Misumi, I., Whitmire, J. K., Atkins, H. M., Lazear, H. M.. 2023-09-14. Interferon lambda restricts herpes simplex virus skin disease by suppressing neutrophil-mediated pathology. https://doi.org/10.1101/2023.09.11.557277

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