Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood
| Autor: | Damien Chaussabel, Yi Hung Ou, Flore Rozenberg, Rebeca Pérez de Diego, Pierre Lebon, Laurent Abel, Shen-Ying Zhang, Melina Herman, Marc Tardieu, Annabelle Cardon, Vanessa Sancho-Shimizu, Elisabeth Israelsson, Maja Klaudel-Dreszler, Yiqi Guo, Elodie Pauwels, Michael A. White, Jean-Laurent Casanova, Avinash Abhyankar, Michael J. Ciancanelli, Lazaro Lorenzo, Edyta Heropolitańska-Pliszka |
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| Rok vydání: | 2012 |
| Předmět: |
Male
viruses animal diseases Immunology Herpesvirus 1 Human Biology Protein Serine-Threonine Kinases Article 03 medical and health sciences Mice 0302 clinical medicine fluids and secretions TANK-binding kinase 1 Immunity Immunology and Allergy Animals Humans Kinase activity Allele Child Cells Cultured 030304 developmental biology Dominance (genetics) Genes Dominant 0303 health sciences Cell Death fungi technology industry and agriculture food and beverages Heterozygote advantage Interferon-beta Vesiculovirus Fibroblasts Phenotype Virology 3. Good health Toll-Like Receptor 3 Poly I-C Viral replication Mutation Female Encephalitis Herpes Simplex 030217 neurology & neurosurgery |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 |
| Popis: | Two unrelated children with HSE carry distinct heterozygous mutations in the gene encoding TANK-binding kinase 1. Childhood herpes simplex virus-1 (HSV-1) encephalitis (HSE) may result from single-gene inborn errors of TLR3 immunity. TLR3-dependent induction of IFN-α/β or IFN-λ is crucial for protective immunity against primary HSV-1 infection in the central nervous system (CNS). We describe here two unrelated children with HSE carrying different heterozygous mutations (D50A and G159A) in TBK1, the gene encoding TANK-binding kinase 1, a kinase at the crossroads of multiple IFN-inducing signaling pathways. Both mutant TBK1 alleles are loss-of-function but through different mechanisms: protein instability (D50A) or a loss of kinase activity (G159A). Both are also associated with an autosomal-dominant (AD) trait but by different mechanisms: haplotype insufficiency (D50A) or negative dominance (G159A). A defect in polyinosinic-polycytidylic acid–induced TLR3 responses can be detected in fibroblasts heterozygous for G159A but not for D50A TBK1. Nevertheless, viral replication and cell death rates caused by two TLR3-dependent viruses (HSV-1 and vesicular stomatitis virus) were high in fibroblasts from both patients, and particularly so in G159A TBK1 fibroblasts. These phenotypes were rescued equally well by IFN-α2b. Moreover, the IFN responses to the TLR3-independent agonists and viruses tested were maintained in both patients’ peripheral blood mononuclear cells and fibroblasts. The narrow, partial cellular phenotype thus accounts for the clinical phenotype of these patients being limited to HSE. These data identify AD partial TBK1 deficiency as a new genetic etiology of childhood HSE, indicating that TBK1 is essential for the TLR3- and IFN-dependent control of HSV-1 in the CNS. |
| Databáze: | OpenAIRE |
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