Identification and characterization of collagen XXIII alpha 1 as a novel risk factor for eczema herpeticum

Abstract Background: A subgroup of atopic dermatitis (AD) patients is prone to develop severe, disseminated cutaneous infection with herpes simplex virus (HSV), known as eczema herpeticum (EH). The occurrence of EH in a subset of AD patients and its frequent recurrence implies the importance of genetic factors in its pathogenesis. Objective: We aimed to identify novel genetic risk factors for EH and study their impact on HSV-1 infection. Methods: We performed whole exome sequencing on nine AD patients with (ADEH+) and without (ADEH-) a history of EH in comparison to healthy controls. We validated the finding of a variant of COL23A1 gene (encoding Collagen type XXIII alpha 1 chain) in ADEH in a larger cohort of 117 ADEH+, 117 ADEH- patients and 118 healthy controls by PCR. We studied the expression of COL23A1 in keratinocytes from ADEH+ and ADEH- patients, and the upregulated COL23A1 expression in primary keratinocytes and in the cell line HaCaT to study its role in HSV-1 infection. Results: We identified a single nucleotide polymorphism (SNP), rs2973744 in COL23A1, as a risk factor for EH observed in 5% of ADEH+ patients, 1.6% of healthy donors and 0% of ADEH- patients. Primary human keratinocytes from an ADEH+ patient with SNP rs2973744 expressed higher COL23A1 levels and were more susceptible to HSV-1 than keratinocytes from ADEH- patients. In functional assays we showed that HSV-1 gene expression and cell-to-cell spread was more efficient in keratinocytes with increased expression of COL23A1. Moreover, COL23A1 overexpression in HaCaT cells resulted in transcriptional downregulation of several genes that are involved in an effective immune response (IL1R1, IL32, TLR4, CFH, C3, S100A9, IRF1, and ADAM23) and a notable upregulation of TNC and SPINK5 that are associated with AD. Conclusion: Upregulation of COL23A1 promotes HSV-1 infection presumably by attenuating antiviral responses of keratinocytes. Among other markers, the COL23A1 SNP rs2973744 could be included in the screening of AD patients to identify patients at risk of EH, thus allowing early initiation of therapy.