title: Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis.
abstract: Tumor necrosis factor (TNF) receptor-associated factor 3 (TRAF3) functions downstream of multiple TNF receptors and receptors that induce interferon-α (IFN-α), IFN-β, and IFN-λ production, including Toll-like receptor 3 (TLR3), which is deficient in some patients with herpes simplex virus-1 encephalitis (HSE). Mice lacking TRAF3 die in the neonatal period, preventing direct investigation of the role of TRAF3 in immune responses and host defenses in vivo. Here, we report autosomal dominant, human TRAF3 deficiency in a young adult with a history of HSE in childhood. The TRAF3 mutant allele is loss-of-expression, loss-of-function, dominant-negative and associated with impaired, but not abolished, TRAF3-dependent responses upon stimulation of both TNF receptors and receptors that induce IFN production. TRAF3 deficiency is associated with a clinical phenotype limited to HSE resulting from the impairment of TLR3-dependent induction of IFN. Thus, TLR3-mediated immunity against primary infection by HSV-1 in the central nervous system is critically dependent on TRAF3.
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U980, Necker Medical School, Paris, France.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Pérez de Diego
authors.forename: Vanessa
authors.initials: V
authors.lastname: Sancho-Shimizu
authors.forename: Lazaro
authors.initials: L
authors.lastname: Lorenzo
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.forename: Sabine
authors.initials: S
authors.lastname: Plancoulaine
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Melina
authors.initials: M
authors.lastname: Herman
authors.forename: Annabelle
authors.initials: A
authors.lastname: Cardon
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.forename: Sivakumar
authors.initials: S
authors.lastname: Vallabhapurapu
authors.forename: Jerónimo
authors.initials: J
authors.lastname: Bravo
authors.forename: Klaus
authors.initials: K
authors.lastname: Warnatz
authors.forename: Yves
authors.initials: Y
authors.lastname: Chaix
authors.forename: Françoise
authors.initials: F
authors.lastname: Cascarrigny
authors.forename: Pierre
authors.initials: P
authors.lastname: Lebon
authors.forename: Flore
authors.initials: F
authors.lastname: Rozenberg
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Marc
authors.initials: M
authors.lastname: Tardieu
authors.forename: Saleh
authors.initials: S
authors.lastname: Al-Muhsen
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Jouanguy
authors.forename: Shen-Ying
authors.initials: SY
authors.lastname: Zhang
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D002478:Cells, Cultured; D004198:Disease Susceptibility; D020803:Encephalitis, Herpes Simplex / Q000276:immunology*; D006801:Humans; D007372:Interferons / Q000502:physiology; D009154:Mutation; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000502:physiology*; D051196:Toll-Like Receptor 3 / Q000502:physiology*
chemical_list: D018124:Receptors, Tumor Necrosis Factor; C495344:TLR3 protein, human; D048008:TNF Receptor-Associated Factor 3; C090656:TRAF3 protein, human; D051196:Toll-Like Receptor 3; D007372:Interferons