<i>Ex Vivo</i>
            Infection of Human Skin Models with Herpes Simplex Virus 1: Accessibility of the Receptor Nectin-1 during Formation or Impairment of Epidermal Barriers Is Restricted by Tight Junctions

Cruz, Nydia C. De La; Möckel, Maureen; Niehues, Hanna; Rübsam, Matthias; Malter, Wolfram; Zinser, Max; Krummenacher, Claude; Knebel-Mörsdorf, Dagmar

doi:10.1128/jvi.00262-23

Cited by 4 publications

References 47 publications

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The antimicrobial protein RNase 7 directly restricts herpes simplex virus infection of human keratinocytes

Zeitvogel,

Döhner,

Klug

et al. 2024

Journal of Medical Virology

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Approximately 22% of moderately to severely affected atopic dermatitis (AD) patients have a history of eczema herpeticum, a disseminated rash primarily caused by herpes simplex virus type 1 (HSV‐1). Reduced activity of antimicrobial peptides may contribute to the increased susceptibility of AD patients to HSV‐1. We previously demonstrated that the antimicrobial protein RNase 7 limits HSV‐1 infection of human keratinocytes by promoting self‐DNA sensing. Here, we addressed whether RNase 7 has any effect on HSV‐1 infection when infecting keratinocytes without exogenously added costimulatory DNA, and which step(s) of the infection cycle RNase 7 interferes with. We quantified viral gene expression by RT‐qPCR and flow cytometry, viral genome replication by qPCR, virucidal effects by plaque titration, and plaque formation and the subcellular localization of incoming HSV‐1 particles by microscopy. Recombinant RNase 7 restricted HSV‐1 gene expression, genome replication, and plaque formation in human keratinocytes. It decreased HSV‐1 immediate‐early transcripts independently of the induction of interferon‐stimulated genes. Its main effect was on intracellular infection processes and not on extracellular virions or virus binding to cells. RNase 7 reduced the amount of cell‐associated capsids and the HSV‐1 envelope glycoprotein D at 3 but not at 0.5 h postinfection. Our data show that RNase 7 directly restricts HSV‐1 infection of human keratinocytes, possibly by promoting the degradation of incoming HSV‐1 particles. This suggests that RNase 7 may limit HSV‐1 spread in the skin and that mechanisms that reduce its activity in the lesional skin of AD patients may increase their susceptibility to eczema herpeticum.

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The antimicrobial protein RNase 7 directly restricts herpes simplex virus infection of human keratinocytes

Zeitvogel,

Döhner,

Klug

et al. 2024

Journal of Medical Virology

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Herpes simplex virus: An immunopathologic review

Scott,

Burkhart

2024

JAAD Reviews

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

Chopra,

Roesner,

Döhner

et al. 2024

Preprint

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BackgroundA 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.ObjectiveWe aimed to identify novel genetic risk factors for EH and study their impact on HSV-1 infection.MethodsWe 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.ResultsWe identified a single nucleotide polymorphism (SNP), rs2973744 inCOL23A1, 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,COL23A1overexpression 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, andADAM23) and a notable upregulation ofTNCandSPINK5that are associated with AD.ConclusionUpregulation of COL23A1 promotes HSV-1 infection presumably by attenuating antiviral responses of keratinocytes. Among other markers, theCOL23A1SNP rs2973744 could be included in the screening of AD patients to identify patients at risk of EH, thus allowing early initiation of therapy.

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Ex Vivo Infection of Human Skin Models with Herpes Simplex Virus 1: Accessibility of the Receptor Nectin-1 during Formation or Impairment of Epidermal Barriers Is Restricted by Tight Junctions

Abstract: Herpes simplex virus 1 (HSV-1) is a widely distributed human pathogen which productively infects epithelia. The open question is which barriers of the highly protected epithelia must the virus overcome to reach its receptor nectin-1.

Cited by 4 publications

References 47 publications

The antimicrobial protein RNase 7 directly restricts herpes simplex virus infection of human keratinocytes

The antimicrobial protein RNase 7 directly restricts herpes simplex virus infection of human keratinocytes

Herpes simplex virus: An immunopathologic review

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

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