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-β family ligand activin A was upregulated ten-fold in infected skin. Topically-applied ALK5/TGβR1 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/TGFβR1 signaling may provide a novel co-therapeutic approach, together with VIG, to limit cutaneous spread of vaccinia.
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CITATION STYLE
He, Y., Sultana, I., Takeda, K., & Reed, J. L. (2017). Cutaneous deficiency of filaggrin and STAT3 exacerbates vaccinia disease in vivo. PLoS ONE, 12(1). https://doi.org/10.1371/journal.pone.0170070