Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency
Vanessa Sancho-Shimizu, … , Saleh Al-Muhsen, Jean-Laurent Casanova
Vanessa Sancho-Shimizu, … , Saleh Al-Muhsen, Jean-Laurent Casanova
Published November 21, 2011
Citation Information: J Clin Invest. 2011;121(12):4889-4902. https://doi.org/10.1172/JCI59259.
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Research Article Immunology

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

Vanessa Sancho-Shimizu, Rebeca Pérez de Diego, Lazaro Lorenzo, Rabih Halwani, Abdullah Alangari, Elisabeth Israelsson, Sylvie Fabrega,, Annabelle Cardon, Jerome Maluenda, Megumi Tatematsu, Farhad Mahvelati, Melina Herman, Michael Ciancanelli, Yiqi Guo, Zobaida AlSum, Nouf Alkhamis, Abdulkarim S. Al-Makadma, Ata Ghadiri, Soraya Boucherit, Sabine Plancoulaine, Capucine Picard, Flore Rozenberg, Marc Tardieu, Pierre Lebon, Emmanuelle Jouanguy, Nima Rezaei, Tsukasa Seya, Misako Matsumoto, Damien Chaussabel, Anne Puel, Shen-Ying Zhang, Laurent Abel, Saleh Al-Muhsen, Jean-Laurent Casanova

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Figure 1

AR TRIF deficiency in P1.

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AR TRIF deficiency in P1. (A) Family pedigree of kindred A with allele s...
(A) Family pedigree of kindred A with allele segregation of the mutation. The HSE patient is shaded in black. Roman numerals (left margin) indicate generations. An arrow indicates the proband. (B) Automated sequencing profiles for the TRIF C421>T mutation in gDNA isolated from leukocytes from a healthy unrelated control; the patient, P1; and the father, I.2. The arrow indicates the position of the mutation. (C) A schematic representation of the TRIF protein (1–712 amino acids) indicating the amino acid position, R141X, affected by the C421>T mutation. Proline-rich domains (pro rich) are shaded in gray; functional domains are shaded in black (TRAF6 binding, TIR, RIP homotypic interacting motif [RHIM]). (D) TRIF protein expression by immunoblot analysis of SV40 fibroblast cell lysates from a healthy control (C+) and P1. Samples were migrated on the same blot. TRIF expression levels were quantified by densitometry results normalized with respect to ACTIN levels and expressed as relative intensity of TRIF. This is a representative blot from 3 independent experiments (mean ± SEM). (E) RT-PCR of full-length TRIF cDNA is shown with ACTB cDNA as an internal control. TRIF cDNA levels were assessed by real-time PCR in control fibroblasts (C+) and P1. Data are represented as relative fold change (ΔΔCt units), where GUS was used for normalization. An average of 3 independent experiments is represented (mean ± SEM).