Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity

A new autosomal recessive form of complete TLR3 deficiency reveals that human TLR3 is nonredundant in immunity against herpes simplex virus 1 in the central nervous system (CNS) but redundant in host defense against viruses outside the CNS

Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis

11 pages, 6 figures.- PMID: 20832341 [PubMed]PMCID: PMC2946444 [Available on 2011/9/1]Tumor necrosis factor (TNF) receptor-associated factor 3 (TRAF3) functions downstream of multiple TNF receptors and receptors that induce interferon-alpha (IFN-alpha), IFN-beta, and IFN-lambda 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 TRAF3This study was supported by the AXA Research fund, the Schlumberger Foundation, the BNP-Paribas Foundation, the Groupement d’Intérêt Scientifique Maladies Rares, the Action Concertée Incitative de Microbiologie, the March of Dimes, the Agence Nationale pour la Recherche, the Eppley Foundation, the National Institute of Allergy and Infectious Diseases grant number 1R01AI088364, the Thrasher Research Fund, the Jeffrey Modell Foundation and Talecris Biotherapeutics, the St. Giles Foundation, the Rockefeller University Center for Clinical and Translational Science grant number 5UL1RR024143, and the Rockefeller University. P.R. is supported by a European Union FP6 grant. J.-L.C. was an international scholar of the Howard Hughes Medical Institute until 2008.Peer reviewe