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: Rebeca Pérez de Diego, Vanessa Sancho-Shimizu, Lazaro Lorenzo, Anne Puel, Sabine Plancoulaine, Capucine Picard, Melina Herman, Annabelle Cardon, Anne Durandy, Jacinta Bustamante, Sivakumar Vallabhapurapu, Jerónimo Bravo, Klaus Warnatz, Yves Chaix, Françoise Cascarrigny, Pierre Lebon, Flore Rozenberg, Michael Karin, Marc Tardieu, Saleh Al-Muhsen, Emmanuelle Jouanguy, Shen-Ying Zhang, Laurent Abel, Jean-Laurent Casanova
• Journal: Immunity (Immunity) Vol. 33 Issue 3 Pg. 400-11 (Sep 24 2010) ISSN: 1097-4180 [Electronic] United States
• PMID: 20832341 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Inc. All rights reserved.

Chemical References

• Receptors, Tumor Necrosis Factor
• TLR3 protein, human
• TNF Receptor-Associated Factor 3
• TRAF3 protein, human
• Toll-Like Receptor 3
• Interferons

Topics

• Cells, Cultured
• Disease Susceptibility
• Encephalitis, Herpes Simplex (immunology)
• Humans
• Interferons (physiology)
• Mutation
• Receptors, Tumor Necrosis Factor (physiology)
• TNF Receptor-Associated Factor 3 (genetics, physiology)
• Toll-Like Receptor 3 (physiology)