Small molecule inhibition of activin receptor signaling limits vaccinia virus growth in the skin of a new filaggrin-deficient murine model of eczema vaccinatum

Authors

• Y He
• I Sultana
• K Takeda
• JL Reed

Abstract

Eczema vaccinatum (EV) is a potentially fatal disseminated infection that occasionally occurs after smallpox vaccination in a subset of persons with atopic dermatitis (AD) or other skin disorders. Should a return to widespread smallpox vaccination be required, thousands of EV cases would be expected, with prolonged hospitalization especially in infants and children and a fatality rate of up to 40% in untreated patients. In historic reports, patients improved with prolonged high-dose vaccinia immune globulin (VIG) treatment. There is not enough VIG available to treat the number of EV cases expected if the US were to return to universal vaccination. Our overarching program goal is to identify potential VIG-sparing treatments, using an accessible EV model with the salient features of human disease. We have developed immunodeficient mouse models featuring epidermal deficiency in STAT3 and filaggrin, two genes associated with AD and severe skin infections in people. In immunosuppressed animals with combined filaggrin and STAT3 defects in the skin, vaccinia scarification yielded pronounced local and distant viral spread accompanied by elevated levels of the TGF-b family ligand activin A. Small molecule inhibition of activin receptor (ALK5) signaling promoted viral clearance from the skin but not disseminated infection sites. We are currently evaluating the role of activin A in shaping innate and adaptive immune responses to skin infection in mice, and testing TGF-b family signaling inhibitors, and other potential co-therapies, to identify VIG-sparing combinations. Data gleaned from these studies could help to improve national preparedness for a possible return to universal smallpox vaccination.

Scientific Focus Area: Virology

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