Cargando…
Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2012
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428952/ https://www.ncbi.nlm.nih.gov/pubmed/22851595 http://dx.doi.org/10.1084/jem.20111316 |
_version_ | 1782241748885438464 |
---|---|
author | Herman, Melina Ciancanelli, Michael Ou, Yi-Hung Lorenzo, Lazaro Klaudel-Dreszler, Maja Pauwels, Elodie Sancho-Shimizu, Vanessa Pérez de Diego, Rebeca Abhyankar, Avinash Israelsson, Elisabeth Guo, Yiqi Cardon, Annabelle Rozenberg, Flore Lebon, Pierre Tardieu, Marc Heropolitańska-Pliszka, Edyta Chaussabel, Damien White, Michael A. Abel, Laurent Zhang, Shen-Ying Casanova, Jean-Laurent |
author_facet | Herman, Melina Ciancanelli, Michael Ou, Yi-Hung Lorenzo, Lazaro Klaudel-Dreszler, Maja Pauwels, Elodie Sancho-Shimizu, Vanessa Pérez de Diego, Rebeca Abhyankar, Avinash Israelsson, Elisabeth Guo, Yiqi Cardon, Annabelle Rozenberg, Flore Lebon, Pierre Tardieu, Marc Heropolitańska-Pliszka, Edyta Chaussabel, Damien White, Michael A. Abel, Laurent Zhang, Shen-Ying Casanova, Jean-Laurent |
author_sort | Herman, Melina |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3428952 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-34289522013-02-27 Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood Herman, Melina Ciancanelli, Michael Ou, Yi-Hung Lorenzo, Lazaro Klaudel-Dreszler, Maja Pauwels, Elodie Sancho-Shimizu, Vanessa Pérez de Diego, Rebeca Abhyankar, Avinash Israelsson, Elisabeth Guo, Yiqi Cardon, Annabelle Rozenberg, Flore Lebon, Pierre Tardieu, Marc Heropolitańska-Pliszka, Edyta Chaussabel, Damien White, Michael A. Abel, Laurent Zhang, Shen-Ying Casanova, Jean-Laurent J Exp Med Article 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. The Rockefeller University Press 2012-08-27 /pmc/articles/PMC3428952/ /pubmed/22851595 http://dx.doi.org/10.1084/jem.20111316 Text en © 2012 Herman et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Article Herman, Melina Ciancanelli, Michael Ou, Yi-Hung Lorenzo, Lazaro Klaudel-Dreszler, Maja Pauwels, Elodie Sancho-Shimizu, Vanessa Pérez de Diego, Rebeca Abhyankar, Avinash Israelsson, Elisabeth Guo, Yiqi Cardon, Annabelle Rozenberg, Flore Lebon, Pierre Tardieu, Marc Heropolitańska-Pliszka, Edyta Chaussabel, Damien White, Michael A. Abel, Laurent Zhang, Shen-Ying Casanova, Jean-Laurent Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood |
title | Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood |
title_full | Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood |
title_fullStr | Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood |
title_full_unstemmed | Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood |
title_short | Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood |
title_sort | heterozygous tbk1 mutations impair tlr3 immunity and underlie herpes simplex encephalitis of childhood |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428952/ https://www.ncbi.nlm.nih.gov/pubmed/22851595 http://dx.doi.org/10.1084/jem.20111316 |
work_keys_str_mv | AT hermanmelina heterozygoustbk1mutationsimpairtlr3immunityandunderlieherpessimplexencephalitisofchildhood AT ciancanellimichael heterozygoustbk1mutationsimpairtlr3immunityandunderlieherpessimplexencephalitisofchildhood AT ouyihung heterozygoustbk1mutationsimpairtlr3immunityandunderlieherpessimplexencephalitisofchildhood AT lorenzolazaro heterozygoustbk1mutationsimpairtlr3immunityandunderlieherpessimplexencephalitisofchildhood AT klaudeldreszlermaja heterozygoustbk1mutationsimpairtlr3immunityandunderlieherpessimplexencephalitisofchildhood AT pauwelselodie heterozygoustbk1mutationsimpairtlr3immunityandunderlieherpessimplexencephalitisofchildhood AT sanchoshimizuvanessa heterozygoustbk1mutationsimpairtlr3immunityandunderlieherpessimplexencephalitisofchildhood AT perezdediegorebeca heterozygoustbk1mutationsimpairtlr3immunityandunderlieherpessimplexencephalitisofchildhood AT abhyankaravinash heterozygoustbk1mutationsimpairtlr3immunityandunderlieherpessimplexencephalitisofchildhood AT israelssonelisabeth heterozygoustbk1mutationsimpairtlr3immunityandunderlieherpessimplexencephalitisofchildhood AT guoyiqi heterozygoustbk1mutationsimpairtlr3immunityandunderlieherpessimplexencephalitisofchildhood AT cardonannabelle heterozygoustbk1mutationsimpairtlr3immunityandunderlieherpessimplexencephalitisofchildhood AT rozenbergflore heterozygoustbk1mutationsimpairtlr3immunityandunderlieherpessimplexencephalitisofchildhood AT lebonpierre heterozygoustbk1mutationsimpairtlr3immunityandunderlieherpessimplexencephalitisofchildhood AT tardieumarc heterozygoustbk1mutationsimpairtlr3immunityandunderlieherpessimplexencephalitisofchildhood AT heropolitanskapliszkaedyta heterozygoustbk1mutationsimpairtlr3immunityandunderlieherpessimplexencephalitisofchildhood AT chaussabeldamien heterozygoustbk1mutationsimpairtlr3immunityandunderlieherpessimplexencephalitisofchildhood AT whitemichaela heterozygoustbk1mutationsimpairtlr3immunityandunderlieherpessimplexencephalitisofchildhood AT abellaurent heterozygoustbk1mutationsimpairtlr3immunityandunderlieherpessimplexencephalitisofchildhood AT zhangshenying heterozygoustbk1mutationsimpairtlr3immunityandunderlieherpessimplexencephalitisofchildhood AT casanovajeanlaurent heterozygoustbk1mutationsimpairtlr3immunityandunderlieherpessimplexencephalitisofchildhood |