Human TRAF3 Adaptor Molecule Deficiency Leads to Impaired Toll-like Receptor 3 Response and Susceptibility to Herpes Simplex Encephalitis

• Published in: Immunity (Cambridge, Mass.) Vol. 33; no. 3; pp. 400 - 411
• Main Authors: Pérez de Diego, Rebeca, Sancho-Shimizu, Vanessa, Lorenzo, Lazaro, Puel, Anne, Plancoulaine, Sabine, Picard, Capucine, Herman, Melina, Cardon, Annabelle, Durandy, Anne, Bustamante, Jacinta, Vallabhapurapu, Sivakumar, Bravo, Jerónimo, Warnatz, Klaus, Chaix, Yves, Cascarrigny, Françoise, Lebon, Pierre, Rozenberg, Flore, Karin, Michael, Tardieu, Marc, Al-Muhsen, Saleh, Jouanguy, Emmanuelle, Zhang, Shen-Ying, Abel, Laurent, Casanova, Jean-Laurent
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.09.2010; Elsevier Limited; Elsevier
• Subjects: Cells, Cultured; Disease Susceptibility; Encephalitis, Herpes Simplex - immunology; Herpes simplex virus 1; Humans; Interferons - physiology; Life Sciences; Mortality; Mutagenesis; Mutation; Pathogenesis; Patients; Proteins; Receptors, Tumor Necrosis Factor - physiology; TNF Receptor-Associated Factor 3 - genetics; TNF Receptor-Associated Factor 3 - physiology; Toll-Like Receptor 3 - physiology
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2010.08.014

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. ► Autosomal-dominant TRAF3 deficiency is a genetic etiology of herpes simplex encephalitis ► R118W TRAF3 allele is loss-of-function, loss-of-expression, and dominant-negative ► Human TRAF3 deficiency impairs the TLR3-dependent induction of antiviral interferons.