Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis.
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.
Pérez de Diego
Rebeca
R
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U980, Necker Medical School, Paris, France.
Sancho-Shimizu
Vanessa
V
Lorenzo
Lazaro
L
Puel
Anne
A
Plancoulaine
Sabine
S
Picard
Capucine
C
Herman
Melina
M
Cardon
Annabelle
A
Durandy
Anne
A
Bustamante
Jacinta
J
Vallabhapurapu
Sivakumar
S
Bravo
Jerónimo
J
Warnatz
Klaus
K
Chaix
Yves
Y
Cascarrigny
Françoise
F
Lebon
Pierre
P
Rozenberg
Flore
F
Karin
Michael
M
Tardieu
Marc
M
Al-Muhsen
Saleh
S
Jouanguy
Emmanuelle
E
Zhang
Shen-Ying
SY
Abel
Laurent
L
Casanova
Jean-Laurent
JL
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*
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