Cutaneous Deficiency of Filaggrin and STAT3 Exacerbates Vaccinia Disease In Vivo.
PLoS One
; 12(1): e0170070, 2017.
Article
en En
| MEDLINE
| ID: mdl-28081250
RATIONALE: Defects in filaggrin and STAT3 are associated with atopic dermatitis (AD) and susceptibility to severe skin infection. METHODS: We evaluated skin infection with the current smallpox vaccine, ACAM-2000, in immunosuppressed mice with combined cutaneous deficiency in filaggrin and STAT3. In parallel, early events post-infection with ACAM-2000 were investigated in cultured keratinocytes in which filaggrin expression was knocked down via siRNA. RESULTS: Immunosuppressed, filaggrin-deficient mice, treated with the topical STAT3 inhibitor Stattic® prior to ACAM-2000 infection, demonstrated rapid weight loss, prolonged vaccinia burden in skin, and dermatitis. The TGF-ß family ligand activin A was upregulated ten-fold in infected skin. Topically-applied ALK5/TGßR1 signaling inhibitor synergized with vaccinia immune globulin (VIG) to promote vaccinia clearance and limit weight loss. In cultured keratinocytes, filaggrin-directed siRNA inhibited programmed necrosis and inflammatory cytokine release induced by ACAM-2000, while viral growth was increased. CONCLUSIONS: Our findings may point to a novel role for filaggrin in early antiviral responses in skin. In wounded skin with underlying barrier defects, chronically elevated activin A levels may contribute to skin remodeling and cutaneous pathogen persistence. Inhibition of ALK5/TGFßR1 signaling may provide a novel co-therapeutic approach, together with VIG, to limit cutaneous spread of vaccinia.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Vaccinia
/
Factor de Transcripción STAT3
/
Proteínas de Filamentos Intermediarios
Tipo de estudio:
Etiology_studies
Idioma:
En
Revista:
PLoS One
Asunto de la revista:
CIENCIA
/
MEDICINA
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos