title: The proteome of Toll-like receptor 3-stimulated human immortalized fibroblasts: implications for susceptibility to herpes simplex virus encephalitis.
abstract: BACKGROUND
  Inborn errors in Toll-like receptor 3 (TLR3)-IFN type I and III pathways have been implicated in susceptibility to herpes simplex virus encephalitis (HSE) in children, but most patients studied do not carry mutations in any of the genes presently associated with HSE susceptibility. Moreover, many patients do not display any TLR3-IFN-related fibroblastic phenotype.
  
  
  OBJECTIVE
  To study other signaling pathways downstream of TLR3 and/or other independent pathways that may contribute to HSE susceptibility.
  
  
  METHODS
  We used the stable isotope labeling of amino acids in cell culture proteomics methodology to measure changes in the human immortalized fibroblast proteome after TLR3 activation.
  
  
  RESULTS
  Cells from healthy controls were compared with cells from a patient with a known genetic etiology of HSE (UNC-93B-/-) and also to cells from an HSE patient with an unknown gene defect. Consistent with known variation in susceptibility of individuals to viral infections, substantial variation in the response level of different healthy controls was observed, but common functional networks could be identified, including upregulation of superoxide dismutase 2. The 2 patients with HSE studied show clear differences in functional response networks when compared with healthy controls and also when compared with each other.
  
  
  CONCLUSIONS
  The present study delineates a number of novel proteins, TLR3-related pathways, and cellular phenotypes that may help elucidate the genetic basis of childhood HSE. Furthermore, our results reveal superoxide dismutase 2 as a potential therapeutic target for amelioration of the neurologic sequelae caused by HSE.
authors: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Medical School, and Pediatric Hematology-Immunology Unit, Necker Hospital, Paris, France. rebeca.perez@idipaz.es
authors: Rebeca
authors: R
authors: Pérez de Diego
authors: Claire
authors: C
authors: Mulvey
authors: Mark
authors: M
authors: Crawford
authors: Matthew W B
authors: MW
authors: Trotter
authors: Lazaro
authors: L
authors: Lorenzo
authors: Vanessa
authors: V
authors: Sancho-Shimizu
authors: Laurent
authors: L
authors: Abel
authors: Shen-Ying
authors: SY
authors: Zhang
authors: Jean-Laurent
authors: JL
authors: Casanova
authors: Jasminka
authors: J
authors: Godovac-Zimmermann
mesh_terms: D002648:Child; D020803:Encephalitis, Herpes Simplex / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D005347:Fibroblasts / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D020543:Proteome / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics* / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000235:genetics* / Q000276:immunology; D000099156:Superoxide Dismutase 2
chemical_list: D020543:Proteome; D013482:Superoxide Dismutase; D051196:Toll-Like Receptor 3; D000099156:Superoxide Dismutase 2; C495344:TLR3 protein, human