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

Area of Science:

• Immunology
• Virology
• Dermatology

Background:

• Type III interferons (IFN-λ) are crucial antiviral and immunomodulatory cytokines.
• Their roles in respiratory and gastrointestinal infections are well-established, but skin-specific effects remain underexplored.
• Herpes simplex virus (HSV) is a prevalent human pathogen causing skin infections.

Purpose of the Study:

• To investigate the skin-specific antiviral and immunomodulatory functions of IFN-λ against HSV infections.
• To elucidate the cellular mechanisms by which IFN-λ influences HSV pathogenesis in the skin.

Main Methods:

• Utilized knockout mouse models lacking IFN-λ receptors (Ifnlr1-/-) or IFN-λ cytokines (Ifnl2/3-/-).
• Employed RNA sequencing (RNAseq) to analyze transcriptional responses in primary mouse keratinocytes.
• Investigated the roles of keratinocytes and neutrophils in IFN-λ-mediated control of HSV skin lesions.

Main Results:

• IFN-λ restricts the severity of HSV-1 and HSV-2 skin lesions without impacting viral loads.
• IFN-λ signaling in keratinocytes suppresses CXCL9-mediated neutrophil recruitment to the skin.
• Depleting neutrophils or blocking CXCL9 ameliorated severe HSV-1 skin lesions in Ifnlr1-/- mice.

Conclusions:

• IFN-λ exerts an immunomodulatory role in the skin, restricting neutrophil-driven pathology during HSV infection.
• IFN-λ signaling in both keratinocytes and neutrophils is essential for controlling HSV skin lesion severity.
• These findings highlight potential therapeutic applications of IFN-λ for managing viral skin infections.