Short‐form thymic stromal lymphopoietin (sfTSLP) restricts herpes simplex virus infection of human primary keratinocytes

Abstract Eczema herpeticum (EH) is a disseminated severe herpes simplex virus type 1 (HSV‐1) infection that mainly occurs in a subset of patients suffering from atopic dermatitis (AD). EH is complex and multifaceted, involving immunological changes, environmental influences, and genetic aberrations. Certain genetic variants of the thymic stromal lymphopoietin ( TSLP ) may predispose to develop severe HSV‐1‐induced eczema. Therefore, we investigated the impact of TSLP on HSV‐1 infection. TSLP encodes for two distinct forms: a long‐form (lfTSLP), primarily associated with type 2 immunity, and a short‐form (sfTSLP) with anti‐inflammatory and antimicrobial properties. While sfTSLP reduced HSV‐1 infectibility in human primary keratinocytes (HPK), lfTSLP did not. In HPK treated with sfTSLP, HSV‐1 gene expression, and replication decreased, while virion binding to cells and targeting of incoming capsids to the nucleus were not diminished compared to untreated cells. sfTSLP caused only minor changes in the expression of innate immunity cytokines, and its inhibition of HSV‐1 infection did not require de novo protein synthesis. Time window experiments indicated a different antiviral mechanism than LL‐37. sfTSLP showed the strongest antiviral effect when administered to HPK before or after inoculation with HSV‐1, and outperformed the inhibitory potential of LL‐37 under these conditions. Our data show that sfTSLP has antiviral functions and promotes repression of the HSV‐1 infection in HPK.