Objetivo Herpes simplex encephalitis (HSE) is a rare disease affecting young children as well as adults due to primary infection with herpes simplex virus-1 (HSV-1). HSV-1 is a nearly ubiquitous virus commonly infecting humans however most do not develop HSE, suggesting that these children possess an underlying genetic susceptibility to HSV-1. In addition, familial forms of HSE have been described, and in our HSE epidemiological study a relatively high incidence of consanguinity was found among HSE patients supporting the notion of a genetic contribution to disease manifestation. Notably, these patients are otherwise healthy and able to mount a normal adaptive immune response to HSV-1, pointing to the likelihood that they harbor an unidentified form of primary immunodeficiency disease affecting their innate immune system. We have recently identified the first two genetic etiologies UNC93B and TLR3 deficiencies in HSE patients validating our hypothesis. Here we propose to use a candidate gene approach to identify other gene(s) involved in HSE by cellular phenotyping and physical mapping. The cellular phenotyping will focus on one of the major components of antiviral innate immunity, namely, the production of and response to interferon-α/β (IFN-α/β). Patients with mutations in UNC93B and TLR3 show reduced IFN production after viral and double-stranded RNA stimulation, revealing this specific UNC93B-TLR3-IFN pathway as relevant to HSE immunity. Hence, HSE patients will be screened for IFN production in response to HSV-1 and Toll-like receptor agonists, and the causative genes identified following a candidate gene approach. In parallel, physical mapping has been initiated following the results of a genome scan of consanguineous families with HSE. The identification of genes involved in HSE will present important biological and medical implications, providing a dissection of immunity to HSV-1 in natural conditions and a rational understanding of HSE pathogenesis. Ámbito científico ciencias médicas y de la saludciencias de la saludenfermedad infecciosaciencias médicas y de la saludmedicina básicainmunología Palabras clave Immunology Infections Molecular genetics Programa(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Tema(s) PEOPLE-2007-2-1.IEF - Marie Curie Action: "Intra-European Fellowships for Career Development" Convocatoria de propuestas FP7-PEOPLE-2007-2-1-IEF Consulte otros proyectos de esta convocatoria Régimen de financiación MC-IEF - Intra-European Fellowships (IEF) Coordinador Université Paris Descartes Dirección Rue de l'ecole de médecine 75270 cedex 06 Paris Francia Ver en el mapa Tipo de actividad Higher or Secondary Education Establishments Contacto administrativo Jean Laurent Casanova (Dr.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Aportación de la UE Sin datos
