Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 130, Issue 3, Pages 683-+Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2012.06.019
Keywords
Atopic dermatitis; Staphylococcus aureus; herpes simplex virus; vaccinia virus; alpha-toxin; a disintegrin and metalloprotease 10
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Funding
- National Institutes of Health/National Institute of Allergy and Infectious Diseases Atopic Dermatitis Research Network [HHSN272201000020C, R01 AR41256]
- National Institutes of Health
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Background: Patients with atopic dermatitis (AD) with a history of eczema herpeticum have increased staphylococcal colonization and infections. However, whether Staphylococcus aureus alters the outcome of skin viral infection has not been determined. Objective: We investigated whether S aureus toxins modulated host response to herpes simplex virus (HSV) 1 and vaccinia virus (VV) infections in normal human keratinocytes (NHKs) and in murine infection models. Methods: NHKs were treated with S aureus toxins before incubation of viruses. BALB/c mice were inoculated with S aureus 2 days before VV scarification. Viral loads of HSV-1 and VV were evaluated by using real-time PCR, a viral plaque-forming assay, and immunofluorescence staining. Small interfering RNA duplexes were used to knockdown the gene expression of the cellular receptor of alpha-toxin, a disintegrin and metalloprotease 10 (ADAM10). ADAM10 protein and alpha-toxin heptamers were detected by using Western blot assays. Results: We demonstrate that sublytic staphylococcal alpha-toxin increases viral loads of HSV-1 and VV in NHKs. Furthermore, we demonstrate in vivo that the VV load is significantly greater (P < .05) in murine skin inoculated with an alpha-toxin-producing S aureus strain compared with murine skin inoculated with the isogenic alpha-toxin-deleted strain. The viral enhancing effect of alpha-toxin is mediated by ADAM10 and is associated with its pore-forming property. Moreover, we demonstrate that a-toxin promotes viral entry in NHKs. Conclusion: The current study introduces the novel concept that staphylococcal alpha-toxin promotes viral skin infection and provides a mechanism by which S aureus infection might predispose the host toward disseminated viral infections. (J Allergy Clin Immunol 2012;130:683-91.)
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