RESUMO
BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with increased susceptibility to recurrent skin infections. OBJECTIVE: We sought to determine why a subset of patients with AD have an increased risk of disseminated viral skin infections. METHODS: Human subjects with AD with a history of eczema herpeticum (EH) and various control groups were enrolled. Vaccinia virus (VV) expression was measured by means of PCR and immunofluorescent staining in skin biopsy specimens from each study group after incubation with VV. Transgenic mice with a constitutively active signal transducer and activator of transcription 6 gene (STAT6) were characterized for response to VV skin inoculation. Genotyping for 10 STAT6 single nucleotide polymorphisms (SNPs) was performed in a white patient sample (n = 444). RESULTS: VV gene and protein expression were significantly increased in the skin of patients with EH compared with other subject groups after incubation with VV in vitro. Antibody neutralization of IL-4 and IL-13 resulted in lower VV replication in patients with a history of EH. Mice that expressed a constitutively active STAT6 gene compared with wild-type mice had increased mortality and satellite lesion formation after VV skin inoculation. Significant associations were observed between STAT6 SNPs and EH (rs3024975, rs841718, rs167769, and rs703817) and IFN-γ production. The strongest association was observed for a 2-SNP haplotype (patients with AD with a history of EH vs patients with AD without a history of EH, 24.9% vs 9.2%; P = 5.17 × 10(-6)). CONCLUSION: The STAT6 gene increases viral replication in the skin of patients with AD with a history of EH. Further genetic association studies and functional investigations are warranted.
Assuntos
Dermatite Atópica/complicações , Dermatite Atópica/genética , Erupção Variceliforme de Kaposi/complicações , Erupção Variceliforme de Kaposi/genética , Fator de Transcrição STAT6/genética , Dermatopatias Virais/complicações , Adulto , Animais , Dermatite Atópica/virologia , Imunofluorescência , Predisposição Genética para Doença/genética , Humanos , Erupção Variceliforme de Kaposi/virologia , Camundongos , Camundongos Transgênicos , Polimorfismo de Nucleotídeo Único , Dermatopatias Virais/genética , Vacina Antivariólica/efeitos adversos , Vacínia/complicações , Vacínia/genética , Vaccinia virusRESUMO
Eczema vaccinatum is a potentially fatal, disseminated viral skin infection that develops in individuals with atopic dermatitis after exposure to the vaccinia virus (VV). Despite advances in modern medicine, there are few options for those suffering from disseminated VV infections. Ceragenins (CSAs) are synthetic antimicrobial compounds designed to mimic the structure and function of endogenous antimicrobial peptides (AMPs). We show that CSA-13 exhibits potent antiviral activity against VV by (1) direct antiviral effects against VV; and (2) stimulating the expression of endogenous AMPs with known antiviral activity against VV. In addition, we show that a topical application of CSA-13 penetrates the skin and reduces subsequent satellite lesion formation. This suggests that treatment with CSA-13 may be an intervention for individuals with a disseminated VV skin infection.
