title: Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency.
abstract: Herpes simplex encephalitis (HSE) is the most common sporadic viral encephalitis of childhood. Autosomal recessive (AR) UNC-93B and TLR3 deficiencies and autosomal dominant (AD) TLR3 and TRAF3 deficiencies underlie HSE in some children. We report here unrelated HSE children with AR or AD TRIF deficiency. The AR form of the disease was found to be due to a homozygous nonsense mutation that resulted in a complete absence of the TRIF protein. Both the TLR3- and the TRIF-dependent TLR4 signaling pathways were abolished. The AD form of disease was found to be due to a heterozygous missense mutation, resulting in a dysfunctional protein. In this form of the disease, the TLR3 signaling pathway was impaired, whereas the TRIF-dependent TLR4 pathway was unaffected. Both patients, however, showed reduced capacity to respond to stimulation of the DExD/H-box helicases pathway. To date, the TRIF-deficient patients with HSE described herein have suffered from no other infections. Moreover, as observed in patients with other genetic etiologies of HSE, clinical penetrance was found to be incomplete, as some HSV-1-infected TRIF-deficient relatives have not developed HSE. Our results provide what we believe to be the first description of human TRIF deficiency and a new genetic etiology for HSE. They suggest that the TRIF-dependent TLR4 and DExD/H-box helicase pathways are largely redundant in host defense. They further demonstrate the importance of TRIF for the TLR3-dependent production of antiviral IFNs in the CNS during primary infection with HSV-1 in childhood.
authors: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, Necker Medical School, Paris, France. vanessa.sancho-shimizu@inserm.fr
authors: Vanessa
authors: V
authors: Sancho-Shimizu
authors: Rebeca
authors: R
authors: Pérez de Diego
authors: Lazaro
authors: L
authors: Lorenzo
authors: Rabih
authors: R
authors: Halwani
authors: Abdullah
authors: A
authors: Alangari
authors: Elisabeth
authors: E
authors: Israelsson
authors: Sylvie
authors: S
authors: Fabrega
authors: Annabelle
authors: A
authors: Cardon
authors: Jerome
authors: J
authors: Maluenda
authors: Megumi
authors: M
authors: Tatematsu
authors: Farhad
authors: F
authors: Mahvelati
authors: Melina
authors: M
authors: Herman
authors: Michael
authors: M
authors: Ciancanelli
authors: Yiqi
authors: Y
authors: Guo
authors: Zobaida
authors: Z
authors: AlSum
authors: Nouf
authors: N
authors: Alkhamis
authors: Abdulkarim S
authors: AS
authors: Al-Makadma
authors: Ata
authors: A
authors: Ghadiri
authors: Soraya
authors: S
authors: Boucherit
authors: Sabine
authors: S
authors: Plancoulaine
authors: Capucine
authors: C
authors: Picard
authors: Flore
authors: F
authors: Rozenberg
authors: Marc
authors: M
authors: Tardieu
authors: Pierre
authors: P
authors: Lebon
authors: Emmanuelle
authors: E
authors: Jouanguy
authors: Nima
authors: N
authors: Rezaei
authors: Tsukasa
authors: T
authors: Seya
authors: Misako
authors: M
authors: Matsumoto
authors: Damien
authors: D
authors: Chaussabel
authors: Anne
authors: A
authors: Puel
authors: Shen-Ying
authors: SY
authors: Zhang
authors: Laurent
authors: L
authors: Abel
authors: Saleh
authors: S
authors: Al-Muhsen
authors: Jean-Laurent
authors: JL
authors: Casanova
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D000595:Amino Acid Sequence; D002675:Child, Preschool; D018389:Codon, Nonsense; D003241:Consanguinity; D053487:DEAD-box RNA Helicases / Q000502:physiology; D020803:Encephalitis, Herpes Simplex / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D005808:Genes, Recessive; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D018259:Herpesvirus 1, Human; D006801:Humans; D007223:Infant; D016898:Interferon-alpha / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D012529:Saudi Arabia; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology; D051196:Toll-Like Receptor 3 / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D018389:Codon, Nonsense; D016898:Interferon-alpha; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D053487:DEAD-box RNA Helicases