Cutaneous Deficiency of Filaggrin and STAT3 Exacerbates Vaccinia Disease In Vivo

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.