Identification and characterization of collagen XXIII alpha 1 as 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 patients with atopic dermatitis (AD). Genetic factors play a pivotal role in EH development. Herein, we identify a single nucleotide polymorphism (SNP) rs2973744 in the gene encoding collagen XXIII alpha 1 chain (Col23a1) as a novel genetic risk factor for EH using whole exome sequencing. EH-patient-derived primary keratinocytes carrying the SNP rs2973744 show elevated COL23A1 mRNA and total protein levels as well as increased susceptibility to HSV-1. We discover that increasing Col23a1 levels enhances HSV-1 infection in human keratinocytes. The transcriptomic analysis unveils that COL23A1 overexpression dampens keratinocyte immune responses, thereby elucidating the molecular mechanism underlying exacerbated HSV-1 susceptibility. Our findings report a novel potential screening marker and therapeutic target for EH and reveal Col23a1’s unexplored role in HSV-1 pathogenesis.