title: Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood.
abstract: 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.
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Melina
authors.initials: M
authors.lastname: Herman
authors.forename: Michael
authors.initials: M
authors.lastname: Ciancanelli
authors.forename: Yi-Hung
authors.initials: YH
authors.lastname: Ou
authors.forename: Lazaro
authors.initials: L
authors.lastname: Lorenzo
authors.forename: Maja
authors.initials: M
authors.lastname: Klaudel-Dreszler
authors.forename: Elodie
authors.initials: E
authors.lastname: Pauwels
authors.forename: Vanessa
authors.initials: V
authors.lastname: Sancho-Shimizu
authors.forename: Rebeca
authors.initials: R
authors.lastname: Pérez de Diego
authors.forename: Avinash
authors.initials: A
authors.lastname: Abhyankar
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Israelsson
authors.forename: Yiqi
authors.initials: Y
authors.lastname: Guo
authors.forename: Annabelle
authors.initials: A
authors.lastname: Cardon
authors.forename: Flore
authors.initials: F
authors.lastname: Rozenberg
authors.forename: Pierre
authors.initials: P
authors.lastname: Lebon
authors.forename: Marc
authors.initials: M
authors.lastname: Tardieu
authors.forename: Edyta
authors.initials: E
authors.lastname: Heropolitanska-Pliszka
authors.forename: Damien
authors.initials: D
authors.lastname: Chaussabel
authors.forename: Michael A
authors.initials: MA
authors.lastname: White
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.forename: Shen-Ying
authors.initials: SY
authors.lastname: Zhang
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D000818:Animals; D016923:Cell Death / Q000276:immunology; D002478:Cells, Cultured; D002648:Child; D020803:Encephalitis, Herpes Simplex / Q000235:genetics* / Q000276:immunology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000821:virology; D005799:Genes, Dominant; D018259:Herpesvirus 1, Human / Q000472:pathogenicity; D006801:Humans; D016899:Interferon-beta / Q000276:immunology; D008297:Male; D051379:Mice; D009154:Mutation; D011070:Poly I-C / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000276:immunology*; D018116:Vesiculovirus / Q000472:pathogenicity
chemical_list: C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D016899:Interferon-beta; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D011070:Poly I-C