Keratinocyte Priming by Staphylococcus aureus Reduces HSV-1 Susceptibility

Individuals with atopic dermatitis (AD) are at increased risk for skin infections, including eczema herpeticum (EH), a severe condition caused by herpes simplex virus type 1 (HSV-1). While AD skin is often colonized by Staphylococcus aureus (S. aureus), its role in EH susceptibility remains unclear. Here we aim to investigate differences in the skin microbiome of AD patients with (ADEH⁺) and without (ADEH^-) EH and examine the impact of S. aureus and S. epidermidis on HSV-1 infection in an in vitro keratinocyte model.

16S microbiome sequencing was performed on skin samples from ADEH⁺, ADEH^-, and healthy controls. To investigate microbial effects on HSV-1 infection, keratinocytes were pre-incubated with heat-killed S. aureus (HKSA) or S. epidermidis (HKSE), followed by HSV-1 infection in the presence or absence of the Th2 cytokines IL-4 and IL-13, simulating the conditions of AD lesional skin. Infection rates and transcriptomic changes were analyzed.

ADEH⁺ patients showed a reduced microbial diversity compared to ADEH^-, with increased S. aureus and S. epidermidis colonization. HKSA, but not HKSE, protected keratinocytes from HSV-1 infection and reduced the release of infectious progeny virus. Transcriptome analysis of keratinocytes revealed HKSA-induced upregulation of interferon pathways and antimicrobial peptides, and downregulation of HSV-1 entry factors.

Pre-incubation with S. aureus set basal keratinocytes into an alarmed state, restricting HSV-1 infection presumably via downregulation of receptors important for viral entry and activation of antiviral pathways.