Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood

Melina Herman, Michael Ciancanelli, Yi Hung Ou, Lazaro Lorenzo, Maja Klaudel-Dreszler, Elodie Pauwels, Vanessa Sancho-Shimizu, Rebeca Pérez de Diego, Avinash Abhyankar, Elisabeth Israelsson, Yiqi Guo, Annabelle Cardon, Flore Rozenberg, Pierre Lebon, Marc Tardieu, Edyta Heropolitańska-Pliszka, Damien J. Chaussabel, Michael A. White, Laurent Abel, Shen Ying ZhangJean Laurent Casanova

Research output: Contribution to journalArticle

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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-γ 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.

Original languageEnglish
Pages (from-to)1567-1582
Number of pages16
JournalJournal of Experimental Medicine
Volume209
Issue number9
DOIs
Publication statusPublished - Aug 2012
Externally publishedYes

Fingerprint

Herpes Simplex Encephalitis
Human Herpesvirus 1
Immunity
Mutation
Encephalitis
Fibroblasts
Phosphotransferases
Viruses
Phenotype
Central Nervous System
Poly I-C
Vesicular Stomatitis
Virus Diseases
Haplotypes
Genes
Blood Cells
Cell Death
Alleles
Mortality

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Herman, M., Ciancanelli, M., Ou, Y. H., Lorenzo, L., Klaudel-Dreszler, M., Pauwels, E., ... Casanova, J. L. (2012). Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood. Journal of Experimental Medicine, 209(9), 1567-1582. https://doi.org/10.1084/jem.20111316

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 J.; White, Michael A.; Abel, Laurent; Zhang, Shen Ying; Casanova, Jean Laurent.

In: Journal of Experimental Medicine, Vol. 209, No. 9, 08.2012, p. 1567-1582.

Research output: Contribution to journalArticle

Herman, M, Ciancanelli, M, Ou, YH, Lorenzo, L, Klaudel-Dreszler, M, Pauwels, E, Sancho-Shimizu, V, Pérez de Diego, R, Abhyankar, A, Israelsson, E, Guo, Y, Cardon, A, Rozenberg, F, Lebon, P, Tardieu, M, Heropolitańska-Pliszka, E, Chaussabel, DJ, White, MA, Abel, L, Zhang, SY & Casanova, JL 2012, 'Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood', Journal of Experimental Medicine, vol. 209, no. 9, pp. 1567-1582. https://doi.org/10.1084/jem.20111316
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 J. ; White, Michael A. ; Abel, Laurent ; Zhang, Shen Ying ; Casanova, Jean Laurent. / Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood. In: Journal of Experimental Medicine. 2012 ; Vol. 209, No. 9. pp. 1567-1582.
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AU - Klaudel-Dreszler, Maja

AU - Pauwels, Elodie

AU - Sancho-Shimizu, Vanessa

AU - Pérez de Diego, Rebeca

AU - Abhyankar, Avinash

AU - Israelsson, Elisabeth

AU - Guo, Yiqi

AU - Cardon, Annabelle

AU - Rozenberg, Flore

AU - Lebon, Pierre

AU - Tardieu, Marc

AU - Heropolitańska-Pliszka, Edyta

AU - Chaussabel, Damien J.

AU - White, Michael A.

AU - Abel, Laurent

AU - Zhang, Shen Ying

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