title: Functional IRF3 deficiency in a patient with herpes simplex encephalitis.
abstract: 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.
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus Research Center for Innate Immunity, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark Department of Molecular Biology and Genetics, Aarhus Research Center for Innate Immunity, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Line Lykke
authors.initials: LL
authors.lastname: Andersen
authors.affiliation: Department of Infectious Diseases, International Center for Immunodeficiency Diseases, Department of Molecular Medicine, Department of Clinical Immunology, Aarhus University Hospital Skejby, 8200 Aarhus, Denmark.
authors.forename: Nanna
authors.initials: N
authors.lastname: Mørk
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus Research Center for Innate Immunity, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark Department of Molecular Biology and Genetics, Aarhus Research Center for Innate Immunity, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Line S
authors.initials: LS
authors.lastname: Reinert
authors.affiliation: Department of Infectious Diseases, International Center for Immunodeficiency Diseases, Department of Molecular Medicine, Department of Clinical Immunology, Aarhus University Hospital Skejby, 8200 Aarhus, Denmark.
authors.forename: Emil
authors.initials: E
authors.lastname: Kofod-Olsen
authors.affiliation: Department of Molecular Genetics, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Narita
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus Research Center for Innate Immunity, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark Department of Molecular Biology and Genetics, Aarhus Research Center for Innate Immunity, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark Department of Infectious Diseases, International Center for Immunodeficiency Diseases, Department of Molecular Medicine, Department of Clinical Immunology, Aarhus University Hospital Skejby, 8200 Aarhus, Denmark.
authors.forename: Sofie E
authors.initials: SE
authors.lastname: Jørgensen
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus Research Center for Innate Immunity, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark Department of Molecular Biology and Genetics, Aarhus Research Center for Innate Immunity, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Kristian A
authors.initials: KA
authors.lastname: Skipper
authors.affiliation: Department of Molecular Medicine, University of Bonn, 53113 Bonn, Germany.
authors.forename: Klara
authors.initials: K
authors.lastname: Höning
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus Research Center for Innate Immunity, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark Department of Molecular Biology and Genetics, Aarhus Research Center for Innate Immunity, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Hans Henrik
authors.initials: HH
authors.lastname: Gad
authors.affiliation: Department of Infectious Diseases, International Center for Immunodeficiency Diseases, Department of Molecular Medicine, Department of Clinical Immunology, Aarhus University Hospital Skejby, 8200 Aarhus, Denmark Department of Infectious Diseases, International Center for Immunodeficiency Diseases, Department of Molecular Medicine, Department of Clinical Immunology, Aarhus University Hospital Skejby, 8200 Aarhus, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Østergaard
authors.affiliation: Department of Infectious Diseases, International Center for Immunodeficiency Diseases, Department of Molecular Medicine, Department of Clinical Immunology, Aarhus University Hospital Skejby, 8200 Aarhus, Denmark.
authors.forename: Torben F
authors.initials: TF
authors.lastname: Ørntoft
authors.affiliation: Department of Molecular Medicine, University of Bonn, 53113 Bonn, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus Research Center for Innate Immunity, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark Department of Molecular Biology and Genetics, Aarhus Research Center for Innate Immunity, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Søren R
authors.initials: SR
authors.lastname: Paludan
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus Research Center for Innate Immunity, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark Department of Molecular Biology and Genetics, Aarhus Research Center for Innate Immunity, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Jacob Giehm
authors.initials: JG
authors.lastname: Mikkelsen
authors.affiliation: Department of Molecular Genetics, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Department of Infectious Diseases, International Center for Immunodeficiency Diseases, Department of Molecular Medicine, Department of Clinical Immunology, Aarhus University Hospital Skejby, 8200 Aarhus, Denmark Department of Infectious Diseases, International Center for Immunodeficiency Diseases, Department of Molecular Medicine, Department of Clinical Immunology, Aarhus University Hospital Skejby, 8200 Aarhus, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Christiansen
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus Research Center for Innate Immunity, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark Department of Molecular Biology and Genetics, Aarhus Research Center for Innate Immunity, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Rune
authors.initials: R
authors.lastname: Hartmann
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus Research Center for Innate Immunity, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark Department of Molecular Biology and Genetics, Aarhus Research Center for Innate Immunity, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark Department of Infectious Diseases, International Center for Immunodeficiency Diseases, Department of Molecular Medicine, Department of Clinical Immunology, Aarhus University Hospital Skejby, 8200 Aarhus, Denmark Department of Infectious Diseases, International Center for Immunodeficiency Diseases, Department of Molecular Medicine, Department of Clinical Immunology, Aarhus University Hospital Skejby, 8200 Aarhus, Denmark trinmoge@rm.dk.
authors.forename: Trine H
authors.initials: TH
authors.lastname: Mogensen
mesh_terms: D000293:Adolescent; D019943:Amino Acid Substitution; D020803:Encephalitis, Herpes Simplex / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D057895:Haploinsufficiency; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000172:deficiency* / Q000378:metabolism; D007370:Interferon Type I / Q000096:biosynthesis / Q000235:genetics; D020125:Mutation, Missense; D010766:Phosphorylation; D055503:Protein Multimerization / Q000235:genetics
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I