title: NEMO is a key component of NF-κB- and IRF-3-dependent TLR3-mediated immunity to herpes simplex virus.
abstract: BACKGROUND
  Children with germline mutations in Toll-like receptor 3 (TLR3), UNC93B1, TNF receptor-associated factor 3, and signal transducer and activator of transcription 1 are prone to herpes simplex virus-1 encephalitis, owing to impaired TLR3-triggered, UNC-93B-dependent, IFN-α/β, and/or IFN-λ-mediated signal transducer and activator of transcription 1-dependent immunity.
  
  
  OBJECTIVE
  We explore here the molecular basis of the pathogenesis of herpes simplex encephalitis in a child with a hypomorphic mutation in nuclear factor-κB (NF-κB) essential modulator, which encodes the regulatory subunit of the inhibitor of the Iκβ kinase complex.
  
  
  METHODS
  The TLR3 signaling pathway was investigated in the patient's fibroblasts by analyses of IFN-β, IFN-λ, and IL-6 mRNA and protein levels, by quantitative PCR and ELISA, respectively, upon TLR3 stimulation (TLR3 agonists or TLR3-dependent viruses). NF-κB activation was assessed by electrophoretic mobility shift assay and interferon regulatory factor 3 dimerization on native gels after stimulation with a TLR3 agonist.
  
  
  RESULTS
  The patient's fibroblasts displayed impaired responses to TLR3 stimulation in terms of IFN-β, IFN-λ, and IL-6 production, owing to impaired activation of both NF-κB and IRF-3. Moreover, vesicular stomatitis virus, a potent IFN-inducer in human fibroblasts, and herpes simplex virus-1, induced only low levels of IFN-β and IFN-λ in the patient's fibroblasts, resulting in enhanced viral replication and cell death, as reported for UNC-93B-deficient fibroblasts.
  
  
  CONCLUSIONS
  Herpes simplex encephalitis may occur in patients carrying NF-κB essential modulator mutations, due to the impairment of NF-κB- and interferon regulatory factor 3-dependent-TLR3-mediated antiviral IFN production.
authors: St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY10065, USA.
authors: Magali
authors: M
authors: Audry
authors: Michael
authors: M
authors: Ciancanelli
authors: Kun
authors: K
authors: Yang
authors: Aurelie
authors: A
authors: Cobat
authors: Huey-Hsuan
authors: HH
authors: Chang
authors: Vanessa
authors: V
authors: Sancho-Shimizu
authors: Lazaro
authors: L
authors: Lorenzo
authors: Tim
authors: T
authors: Niehues
authors: Janine
authors: J
authors: Reichenbach
authors: Xiao-Xia
authors: XX
authors: Li
authors: Alain
authors: A
authors: Israel
authors: Laurent
authors: L
authors: Abel
authors: Jean-Laurent
authors: JL
authors: Casanova
authors: Shen-Ying
authors: SY
authors: Zhang
authors: Emmanuelle
authors: E
authors: Jouanguy
authors: Anne
authors: A
authors: Puel
mesh_terms: D002675:Child, Preschool; D020803:Encephalitis, Herpes Simplex / Q000235:genetics / Q000276:immunology* / Q000821:virology; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D018139:Simplexvirus / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000276:immunology* / Q000378:metabolism
chemical_list: C491731:IKBKG protein, human; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D051550:I-kappa B Kinase