title: Mutations in the TLR3 signaling pathway and beyond in adult patients with herpes simplex encephalitis.
abstract: Herpes simplex encephalitis (HSE) in children has previously been linked to defects in type I interferon production downstream of Toll-like receptor (TLR)3. In the present study, we used whole-exome sequencing to investigate the genetic profile of 16 adult patients with a history of HSE. We identified novel mutations in IRF3, TYK2 and MAVS, molecules involved in generating innate antiviral immune responses, which have not previously been associated with HSE. Moreover, data revealed mutations in TLR3, TRIF, TBK1 and STAT1 known to be associated with HSE in children but not previously described in adults. All discovered mutations were heterozygous missense mutations, the majority of which were associated with significantly decreased antiviral responses to HSV-1 infection and/or the TLR3 agonist poly(I:C) in patient peripheral blood mononuclear cells compared with controls. Altogether, this study demonstrates novel mutations in the TLR3 signaling pathway in molecules previously identified in children, suggesting that impaired innate immunity to HSV-1 may also increase susceptibility to HSE in adults. Importantly, the identification of mutations in innate signaling molecules not directly involved in TLR3 signaling suggests the existence of innate immunodeficiencies predisposing to HSE beyond the TLR3 pathway.
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark.
authors.forename: N
authors.initials: N
authors.lastname: Mørk
authors.affiliation: International Center for Immunodeficiency Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark.
authors.forename: E
authors.initials: E
authors.lastname: Kofod-Olsen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark.
authors.forename: K B
authors.initials: KB
authors.lastname: Sørensen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark.
authors.forename: E
authors.initials: E
authors.lastname: Bach
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital Skejby, Aarhus, Denmark.
authors.forename: T F
authors.initials: TF
authors.lastname: Ørntoft
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark.|International Center for Immunodeficiency Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark.
authors.forename: L
authors.initials: L
authors.lastname: Østergaard
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: S R
authors.initials: SR
authors.lastname: Paludan
authors.affiliation: International Center for Immunodeficiency Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark.|Department of Clinical Immunology, Aarhus University Hospital Skejby, Aarhus, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Christiansen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark.|International Center for Immunodeficiency Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark.|Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: T H
authors.initials: TH
authors.lastname: Mogensen
mesh_terms: D000328:Adult; D020803:Encephalitis, Herpes Simplex / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D009154:Mutation; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000378:metabolism*
chemical_list: C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3