title: Filaggrin deficiency promotes the dissemination of cutaneously inoculated vaccinia virus.
abstract: BACKGROUND
  Eczema vaccinatum is a life-threatening complication of smallpox vaccination in patients with atopic dermatitis (AD) characterized by dissemination of vaccinia virus (VV) in the skin and internal organs. Mutations in the filaggrin (FLG) gene, the most common genetic risk factor for AD, confer a greater risk for eczema herpeticum in patients with AD, suggesting that it impairs the response to cutaneous viral infections.
  
  
  OBJECTIVE
  We sought to determine the effects of FLG deficiency on the response of mice to cutaneous VV inoculation.
  
  
  METHODS
  VV was inoculated by means of scarification of unsensitized skin or skin topically sensitized with ovalbumin in FLG-deficient flaky tail (ft/ft) mice or wild-type (WT) control mice. The sizes of primary and satellite skin lesions were measured, and hematoxylin and eosin staining was performed. VV genome copy numbers and cytokine mRNA levels were measured by using quantitative PCR.
  
  
  RESULTS
  VV inoculation in unsensitized skin of ft/ft mice, independent of the matted hair mutation, resulted in larger primary lesions, more abundant satellite lesions, heavier viral loads in internal organs, greater epidermal thickness, dermal cellular infiltration, and higher local Il17a, Il4, Il13, and Ifng mRNA levels than in WT control mice. VV inoculation at sites of topical ovalbumin application amplified all of these features in ft/ft mice but had no detectable effect in WT control mice. The number of satellite lesions and the viral loads in internal organs after cutaneous VV inoculation were significantly reduced in both unsensitized and topically sensitized ft/ftxIl17a(-/-) mice.
  
  
  CONCLUSIONS
  FLG deficiency predisposes to eczema vaccinatum. This is mediated primarily through production of IL-17A.
authors: Division of Immunology, Boston Children's Hospital and the Department of Medicine, Harvard Medical School, Boston, Mass. Electronic address: michiko.oyoshi@childrens.harvard.edu.
authors: Michiko K
authors: MK
authors: Oyoshi
authors: Division of Immunology, Boston Children's Hospital and the Department of Medicine, Harvard Medical School, Boston, Mass.
authors: Jacqueline
authors: J
authors: Beaupré
authors: Division of Immunology, Boston Children's Hospital and the Department of Medicine, Harvard Medical School, Boston, Mass.
authors: Nicholas
authors: N
authors: Venturelli
authors: Division of Immunology, Boston Children's Hospital and the Department of Medicine, Harvard Medical School, Boston, Mass.
authors: Christopher N
authors: CN
authors: Lewis
authors: Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan.
authors: Yoichiro
authors: Y
authors: Iwakura
authors: Division of Immunology, Boston Children's Hospital and the Department of Medicine, Harvard Medical School, Boston, Mass.
authors: Raif S
authors: RS
authors: Geha
mesh_terms: D000818:Animals; D003876:Dermatitis, Atopic / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D018450:Disease Progression; D005260:Female; D000091344:Filaggrin Proteins; D015870:Gene Expression; D016679:Genome, Viral; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D007381:Intermediate Filament Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D007617:Kaposi Varicelliform Eruption / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000008:administration & dosage; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D012867:Skin / Q000276:immunology / Q000473:pathology / Q000821:virology; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology*
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; C098680:Il17a protein, mouse; D018793:Interleukin-13; D020381:Interleukin-17; D007381:Intermediate Filament Proteins; D012333:RNA, Messenger; D015847:Interleukin-4; D007371:Interferon-gamma; D010047:Ovalbumin
keywords: IL-17A; Vaccinia virus; filaggrin
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