Collagen XXIII (COL23A1): A novel risk factor for eczema herpeticum

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BACKGROUND: Eczema herpeticum (EH) is a potentially life-threatening disseminated skin infection caused by herpes simplex virus (HSV) in a subset of patients with atopic dermatitis (AD). The occurrence of EH in a subset of patients with AD and its frequent recurrence imply the importance of genetic factors in its pathogenesis. OBJECTIVE: We sought to identify novel genetic risk factors for EH and to study their impact on HSV-1 infection. METHODS: Using whole-exome sequencing we identified a heterozygous single nucleotide polymorphism (SNP) in the COL23A1 gene (encoding collagen type XXIII alpha 1 chain or COL23A1) that was associated with EH and validated it by PCR in a larger cohort. We studied the effect of upregulated COL23A1 expression on HSV-1 infection in primary keratinocytes and HaCaT cells and performed bulk RNA sequencing to address the underlying mechanism. RESULTS: Primary keratinocytes derived from patients with EH carrying this heterozygous SNP rs2973744 had elevated COL23A1 mRNA and protein levels as well as an increased susceptibility to HSV-1. Increasing the COL23A1 levels experimentally enhanced HSV-1 infection in human keratinocytes. COL23A1 overexpression elevated syndecan-1 and nectin-1 levels on the cell surface, which are HSV-1 attachment and entry factors, respectively, and downregulated genes involved in antiviral responses, such as IL1R1, IL32, TLR4, IRF1, S100A9, C3, and CFH. CONCLUSIONS: The SNP rs2973744 enhances COL23A1 expression in keratinocytes derived from patients with AD and a history of EH. Upregulation of COL23A1 promotes HSV-1 infection presumably by upregulating the HSV-1 attachment and entry factors syndecan-1 and nectin-1 on the cell surface and attenuating antiviral responses of keratinocytes.

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