title: Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity.
abstract: Autosomal dominant TLR3 deficiency has been identified as a genetic etiology of childhood herpes simplex virus 1 (HSV-1) encephalitis (HSE). This defect is partial, as it results in impaired, but not abolished induction of IFN-β and -λ in fibroblasts in response to TLR3 stimulation. The apparently normal resistance of these patients to other infections, viral illnesses in particular, may thus result from residual TLR3 responses. We report here an autosomal recessive form of complete TLR3 deficiency in a young man who developed HSE in childhood but remained normally resistant to other infections. This patient is compound heterozygous for two loss-of-function TLR3 alleles, resulting in an absence of response to TLR3 activation by polyinosinic-polycytidylic acid (poly(I:C)) and related agonists in his fibroblasts. Moreover, upon infection of the patient's fibroblasts with HSV-1, the impairment of IFN-β and -λ production resulted in high levels of viral replication and cell death. In contrast, the patient's peripheral blood mononuclear cells responded normally to poly(I:C) and to all viruses tested, including HSV-1. Consistently, various TLR3-deficient leukocytes from the patient, including CD14(+) and/or CD16(+) monocytes, plasmacytoid dendritic cells, and in vitro derived monocyte-derived macrophages, responded normally to both poly(I:C) and HSV-1, with the induction of antiviral IFN production. These findings identify a new genetic etiology for childhood HSE, indicating that TLR3-mediated immunity is essential for protective immunity to HSV-1 in the central nervous system (CNS) during primary infection in childhood, in at least some patients. They also indicate that human TLR3 is largely redundant for responses to double-stranded RNA and HSV-1 in various leukocytes, probably accounting for the redundancy of TLR3 for host defense against viruses, including HSV-1, outside the CNS.
authors.affiliation: 1St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY, USA; Laboratory of Human Genetics of Infectious Diseases, National Institute of Health and Medical Research, Paris, France;Necker Medical School, Paris Descartes University, Paris 75015, France.
authors.forename: Yiqi
authors.initials: Y
authors.lastname: Guo
authors.forename: Magali
authors.initials: M
authors.lastname: Audry
authors.forename: Michael
authors.initials: M
authors.lastname: Ciancanelli
authors.forename: Laia
authors.initials: L
authors.lastname: Alsina
authors.forename: Joana
authors.initials: J
authors.lastname: Azevedo
authors.forename: Melina
authors.initials: M
authors.lastname: Herman
authors.forename: Esperanza
authors.initials: E
authors.lastname: Anguiano
authors.forename: Vanessa
authors.initials: V
authors.lastname: Sancho-Shimizu
authors.forename: Lazaro
authors.initials: L
authors.lastname: Lorenzo
authors.forename: Elodie
authors.initials: E
authors.lastname: Pauwels
authors.forename: Paul Bastard
authors.initials: PB
authors.lastname: Philippe
authors.forename: Rebeca
authors.initials: R
authors.lastname: Pérez de Diego
authors.forename: Annabelle
authors.initials: A
authors.lastname: Cardon
authors.forename: Guillaume
authors.initials: G
authors.lastname: Vogt
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Zafitsara Zo
authors.initials: ZZ
authors.lastname: Andrianirina
authors.forename: Flore
authors.initials: F
authors.lastname: Rozenberg
authors.forename: Pierre
authors.initials: P
authors.lastname: Lebon
authors.forename: Sabine
authors.initials: S
authors.lastname: Plancoulaine
authors.forename: Marc
authors.initials: M
authors.lastname: Tardieu
authors.lastname: Valérie Doireau
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Jouanguy
authors.forename: Damien
authors.initials: D
authors.lastname: Chaussabel
authors.forename: Frederic
authors.initials: F
authors.lastname: Geissmann
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Shen-Ying
authors.initials: SY
authors.lastname: Zhang
mesh_terms: D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D020803:Encephalitis, Herpes Simplex / Q000235:genetics / Q000276:immunology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D055106:Genome-Wide Association Study; D006801:Humans; D007109:Immunity / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D008297:Male; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D010375:Pedigree; D011070:Poly I-C / Q000276:immunology / Q000494:pharmacology; D018139:Simplexvirus / Q000235:genetics / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000172:deficiency* / Q000235:genetics; D055815:Young Adult
chemical_list: C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D011070:Poly I-C