The antimicrobial protein RNase 7 directly restricts herpes simplex virus infection of human keratinocytes

Abstract Approximately 22% of moderately to severely affected atopic dermatitis (AD) patients have a history of eczema herpeticum, a disseminated rash primarily caused by herpes simplex virus type 1 (HSV‐1). Reduced activity of antimicrobial peptides may contribute to the increased susceptibility of AD patients to HSV‐1. We previously demonstrated that the antimicrobial protein RNase 7 limits HSV‐1 infection of human keratinocytes by promoting self‐DNA sensing. Here, we addressed whether RNase 7 has any effect on HSV‐1 infection when infecting keratinocytes without exogenously added costimulatory DNA, and which step(s) of the infection cycle RNase 7 interferes with. We quantified viral gene expression by RT‐qPCR and flow cytometry, viral genome replication by qPCR, virucidal effects by plaque titration, and plaque formation and the subcellular localization of incoming HSV‐1 particles by microscopy. Recombinant RNase 7 restricted HSV‐1 gene expression, genome replication, and plaque formation in human keratinocytes. It decreased HSV‐1 immediate‐early transcripts independently of the induction of interferon‐stimulated genes. Its main effect was on intracellular infection processes and not on extracellular virions or virus binding to cells. RNase 7 reduced the amount of cell‐associated capsids and the HSV‐1 envelope glycoprotein D at 3 but not at 0.5 h postinfection. Our data show that RNase 7 directly restricts HSV‐1 infection of human keratinocytes, possibly by promoting the degradation of incoming HSV‐1 particles. This suggests that RNase 7 may limit HSV‐1 spread in the skin and that mechanisms that reduce its activity in the lesional skin of AD patients may increase their susceptibility to eczema herpeticum.