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

Eczema herpeticum (EH) is a potentially life-threatening disseminated skin infection caused by herpes simplex virus (HSV) in a subset of atopic dermatitis (AD) patients. The occurrence of EH in a subset of AD patients and its frequent recurrence imply the importance of genetic factors in its pathogenesis. We aimed to identify novel genetic risk factors for EH and to study their impact on HSV-1 infection. 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. EH-patient-derived primary keratinocytes 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. The SNP rs2973744 enhances COL23A1 expression in ADEH+-derived keratinocytes. 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.