Thèse de doctorat en Génétique Humaine
Sous la direction de Jean-Laurent Casanova.
Soutenue en 2007
à Paris 5 .
L' encéphalite herpétique de l'enfant : défaut génétique humaine sur la voie de signalisation de Toll-like récepteur 3
Pas de résumé disponible.
Herpes simplex virus (HSV)-l encephalitis (HSE) is the most common sporadic viral encephalitis in western countries, the pathogenesis of HSE remains elusive. We hypothesized that HSE may result, in at least some children, from an unidentified form of primary immunodeficiency, associated with a Mendelian susceptibility to HSV-1, with impaired IFN-a-, -ft- and -A-mediated immunity. Our identification of autosomal recessive UNC-93B deficiency in two otherwise healthy HSE patients and autosomal dominant TLR3 deficiency in other two otherwise healthy HSE patients provided the first two genetic aetiologies of isolated HSE. The production of IFN-P and -A, in UNC-93B-deficient and TLR3-heterozygous fibroblasts was impaired upon poly(LC) stimulation and viral infections including HSV-1. Higher virus titres and enhanced cell mortality upon HSV-1 and VSV infection were observed in both UNC93B-deficient and TLR3-heterozygous fibroblasts, rescued with IFN-a, -0 and -A, treatment, indicating a plausible pathogenesis of HSE. However the patients'' blood dendritic cells (DCs) and keratinocytes produced IFNs in response to poly(LC), and most other viruses induced IFNs in a TLR3-independent manner, providing the first clue for the lack oil other severe viral infections in these patients. Human UNC-93B-TLR3-IFNs pathway is thus suggested to be critical for anti-HSV-1 immunity in the CNS, at least in some circumstances, but redundant in host defense to most other virus infections.