title: Cutaneous Deficiency of Filaggrin and STAT3 Exacerbates Vaccinia Disease In Vivo.
abstract: BACKGROUND
  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.
authors.affiliation: Food and Drug Administration, Center for Biologics Evaluation and Research, 10903 New Hampshire Ave., Silver Spring, MD, United States of America.
authors.forename: Yong
authors.initials: Y
authors.lastname: He
authors.affiliation: Food and Drug Administration, Center for Biologics Evaluation and Research, 10903 New Hampshire Ave., Silver Spring, MD, United States of America.
authors.forename: Ishrat
authors.initials: I
authors.lastname: Sultana
authors.affiliation: Food and Drug Administration, Center for Biologics Evaluation and Research, 10903 New Hampshire Ave., Silver Spring, MD, United States of America.
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Food and Drug Administration, Center for Biologics Evaluation and Research, 10903 New Hampshire Ave., Silver Spring, MD, United States of America.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Reed
mesh_terms: D028341:Activins / Q000032:analysis / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003872:Dermatitis / Q000209:etiology / Q000378:metabolism / Q000821:virology; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index; D012867:Skin / Q000378:metabolism; D015854:Up-Regulation; D014615:Vaccinia / Q000150:complications / Q000473:pathology* / Q000821:virology; D014616:Vaccinia virus / Q000276:immunology
chemical_list: D000906:Antibodies; D016207:Cytokines; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D050796:STAT3 Transcription Factor; C422405:activin A; D028341:Activins; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625842:Tgfbr1 protein, mouse