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Functional IRF3 deficiency in a patient with herpes simplex encephalitis
Herpes simplex encephalitis (HSE) in children has previously been linked to defects in type I interferon (IFN) production downstream of Toll-like receptor 3. Here, we describe a novel genetic etiology of HSE by identifying a heterozygous loss-of-function mutation in the IFN regulatory factor 3 (IRF3...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4548062/ https://www.ncbi.nlm.nih.gov/pubmed/26216125 http://dx.doi.org/10.1084/jem.20142274 |
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author | Andersen, Line Lykke Mørk, Nanna Reinert, Line S. Kofod-Olsen, Emil Narita, Ryo Jørgensen, Sofie E. Skipper, Kristian A. Höning, Klara Gad, Hans Henrik Østergaard, Lars Ørntoft, Torben F. Hornung, Veit Paludan, Søren R. Mikkelsen, Jacob Giehm Fujita, Takashi Christiansen, Mette Hartmann, Rune Mogensen, Trine H. |
author_facet | Andersen, Line Lykke Mørk, Nanna Reinert, Line S. Kofod-Olsen, Emil Narita, Ryo Jørgensen, Sofie E. Skipper, Kristian A. Höning, Klara Gad, Hans Henrik Østergaard, Lars Ørntoft, Torben F. Hornung, Veit Paludan, Søren R. Mikkelsen, Jacob Giehm Fujita, Takashi Christiansen, Mette Hartmann, Rune Mogensen, Trine H. |
author_sort | Andersen, Line Lykke |
collection | PubMed |
description | Herpes simplex encephalitis (HSE) in children has previously been linked to defects in type I interferon (IFN) production downstream of Toll-like receptor 3. Here, we describe a novel genetic etiology of HSE by identifying a heterozygous loss-of-function mutation in the IFN regulatory factor 3 (IRF3) gene, leading to autosomal dominant (AD) IRF3 deficiency by haploinsufficiency, in an adolescent female patient with HSE. IRF3 is activated by most pattern recognition receptors recognizing viral infections and plays an essential role in induction of type I IFN. The identified IRF3 R285Q amino acid substitution results in impaired IFN responses to HSV-1 infection and particularly impairs signaling through the TLR3–TRIF pathway. In addition, the R285Q mutant of IRF3 fails to become phosphorylated at S386 and undergo dimerization, and thus has impaired ability to activate transcription. Finally, transduction with WT IRF3 rescues the ability of patient fibroblasts to express IFN in response to HSV-1 infection. The identification of IRF3 deficiency in HSE provides the first description of a defect in an IFN-regulating transcription factor conferring increased susceptibility to a viral infection in the CNS in humans. |
format | Online Article Text |
id | pubmed-4548062 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-45480622016-02-24 Functional IRF3 deficiency in a patient with herpes simplex encephalitis Andersen, Line Lykke Mørk, Nanna Reinert, Line S. Kofod-Olsen, Emil Narita, Ryo Jørgensen, Sofie E. Skipper, Kristian A. Höning, Klara Gad, Hans Henrik Østergaard, Lars Ørntoft, Torben F. Hornung, Veit Paludan, Søren R. Mikkelsen, Jacob Giehm Fujita, Takashi Christiansen, Mette Hartmann, Rune Mogensen, Trine H. J Exp Med Brief Definitive Report Herpes simplex encephalitis (HSE) in children has previously been linked to defects in type I interferon (IFN) production downstream of Toll-like receptor 3. Here, we describe a novel genetic etiology of HSE by identifying a heterozygous loss-of-function mutation in the IFN regulatory factor 3 (IRF3) gene, leading to autosomal dominant (AD) IRF3 deficiency by haploinsufficiency, in an adolescent female patient with HSE. IRF3 is activated by most pattern recognition receptors recognizing viral infections and plays an essential role in induction of type I IFN. The identified IRF3 R285Q amino acid substitution results in impaired IFN responses to HSV-1 infection and particularly impairs signaling through the TLR3–TRIF pathway. In addition, the R285Q mutant of IRF3 fails to become phosphorylated at S386 and undergo dimerization, and thus has impaired ability to activate transcription. Finally, transduction with WT IRF3 rescues the ability of patient fibroblasts to express IFN in response to HSV-1 infection. The identification of IRF3 deficiency in HSE provides the first description of a defect in an IFN-regulating transcription factor conferring increased susceptibility to a viral infection in the CNS in humans. The Rockefeller University Press 2015-08-24 /pmc/articles/PMC4548062/ /pubmed/26216125 http://dx.doi.org/10.1084/jem.20142274 Text en © 2015 Andersen 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 | Brief Definitive Report Andersen, Line Lykke Mørk, Nanna Reinert, Line S. Kofod-Olsen, Emil Narita, Ryo Jørgensen, Sofie E. Skipper, Kristian A. Höning, Klara Gad, Hans Henrik Østergaard, Lars Ørntoft, Torben F. Hornung, Veit Paludan, Søren R. Mikkelsen, Jacob Giehm Fujita, Takashi Christiansen, Mette Hartmann, Rune Mogensen, Trine H. Functional IRF3 deficiency in a patient with herpes simplex encephalitis |
title | Functional IRF3 deficiency in a patient with herpes simplex encephalitis |
title_full | Functional IRF3 deficiency in a patient with herpes simplex encephalitis |
title_fullStr | Functional IRF3 deficiency in a patient with herpes simplex encephalitis |
title_full_unstemmed | Functional IRF3 deficiency in a patient with herpes simplex encephalitis |
title_short | Functional IRF3 deficiency in a patient with herpes simplex encephalitis |
title_sort | functional irf3 deficiency in a patient with herpes simplex encephalitis |
topic | Brief Definitive Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4548062/ https://www.ncbi.nlm.nih.gov/pubmed/26216125 http://dx.doi.org/10.1084/jem.20142274 |
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