Specificity protein 1 is pivotal in the skin’s antiviral response

• Published in: Journal of allergy and clinical immunology Vol. 127; no. 2; pp. 430 - 438.e2
• Main Authors: Bin, Lianghua, Howell, Michael D., Kim, Byung Eui, Streib, Joanne E., Hall, Clifton F., Leung, Donald Y.M.
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.02.2011; Elsevier; Elsevier Limited
• Subjects: 2',5'-Oligoadenylate Synthetase - physiology; 2’5’-oligoadenylate synthetase 2; Adult; Allergic diseases; Allergy and Immunology; atopic dermatitis; Biological and medical sciences; biopsy; Bullous diseases of the skin; Cells, Cultured; Dermatitis, Atopic - immunology; Dermatitis, Atopic - virology; Dermatology; DNA; double-stranded RNA-dependent protein kinase; eczema; eczema herpeticum; eIF-2 Kinase - physiology; Eukaryotic Initiation Factor-2 - physiology; explants; Female; gene expression; gene expression regulation; Gene Silencing; genes; Herpes simplex virus 1; Human alphaherpesvirus 1; Human viral diseases; Humans; IFN-γ; Immunization; Immunopathology; Infectious diseases; interferon-gamma; Interferon-gamma - pharmacology; Kaposi Varicelliform Eruption - immunology; Kaposi Varicelliform Eruption - virology; keratinocytes; Keratinocytes - virology; Kinases; Male; Medical sciences; Middle Aged; patients; protein kinases; quantitative polymerase chain reaction; Skin - immunology; Skin - virology; Skin allergic diseases. Stinging insect allergies; small interfering RNA; Smallpox; Sp1 Transcription Factor - genetics; Sp1 Transcription Factor - physiology; Specificity protein 1; transcription factors; Vaccines; Vaccinia virus; Vaccinia virus - physiology; Viral diseases; Viral diseases with cutaneous or mucosal lesions and viral diseases of the eye; Viral infections; Virus Replication; Western blotting; OAS; VV; AD; EH; Specificity protein 1; MOI; GO; atopic dermatitis; siRNA; vaccinia virus; KLK; eczema herpeticum; eIF2α; NHK; EV; MFI; IFN-γ; HSV-1; PKR; double-stranded RNA-dependent protein kinase; ADEH; herpes simplex virus 1; 2’5’-oligoadenylate synthetase 2; Sp; Small interfering RNA; Gene ontogeny; Specificity protein; Eukaryotic initiation factor 2α; 2’5’-Oligoadenylate synthetase; Atopic dermatitis without a history of eczema herpeticum; Multiplicity of infection; Mean fluorescence intensity; Kallikrein; Normal human keratinocyte; Atopic dermatitis and a history of eczema herpeticum; Eczema vaccinatum; Allergy; Skin disease; Kaposi-Juliusberg syndrome; Double stranded RNA; Pustulosis dermatosis; Non-specific serine/threonine protein kinase; Alphaherpesvirinae; Atopy; Specificity; Atopic dermatitis; Ligases; Antiviral; Human herpesvirus 1; Immunopathology; Chordopoxvirinae; Enzyme; Herpesviridae; Orthopoxvirus; Transferases; Herpes; Protein; Infection; Virus; Vaccinia virus; Poxviridae; Viral disease; 2'5'-oligoadenylate synthetase 2; Skin; Gamma interferon
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2010.11.013

Previous studies have found specificity protein (Sp) 1 transcription factor in the viral replication machinery and postulated that Sp1 was required for viral replication in host cells. We investigated the role of Sp1 in the skin’s antiviral responses from the perspective of host defense and its biological relevance in patients with atopic dermatitis and a history of eczema herpeticum (ADEH +). Small interfering RNA duplexes were used to knock down Sp1 in keratinocytes. The expression of vaccinia virus (VV), herpes simplex virus 1, and other genes were evaluated by real-time PCR, or combined with Western blot and immunohistofluorescence staining. A total of 106 human subjects participated in this study. Both VV and herpes simplex virus 1 replication were enhanced in Sp1 knocked-down keratinocytes. Sp1 gene expression was significantly decreased in ADEH + subjects compared with patients with atopic dermatitis without a history of eczema herpeticum and nonatopic subjects ( P < .0001) and inversely correlated with VV DNA copy number in human skin explants incubated with VV in vitro (partial correlation r = –0.256; P = .009). Gene profiling revealed that the antiviral genes, double-stranded RNA-dependent protein kinase (PKR) and 2’5’-oligoadenylate synthetase 2 (OAS2), were significantly downregulated in Sp1-silenced keratinocytes. Gene expression of PKR and OAS2 was also significantly decreased in skin biopsies from ADEH + subjects compared with patients with atopic dermatitis without a history of eczema herpeticum and nonatopic subjects. IFN-γ augmented the antiviral capacity of Sp1-silenced keratinocytes. Specificity protein 1 knockdown enhances viral replication in keratinocytes by downregulating gene expression of PKR and OAS2. Sp1 deficiency in ADEH + patients may contribute to their increased propensity to disseminated skin viral infections. IFN-γ augmentation may be a potential treatment for ADEH + patients.