Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency

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 PlancoulaineCapucine Picard, Flore Rozenberg, Marc Tardieu, Pierre Lebon, Emmanuelle Jouanguy, Nima Rezaei, Tsukasa Seya, Misako Matsumoto, Damien J. Chaussabel, Anne Puel, Shen Ying Zhang, Laurent Abel, Saleh Al-Muhsen, Jean Laurent Casanova

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)4889-4902
Number of pages14
JournalJournal of Clinical Investigation
Volume121
Issue number12
DOIs
Publication statusPublished - 1 Dec 2011
Externally publishedYes

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Herpes Simplex Encephalitis
Human Herpesvirus 1
TNF Receptor-Associated Factor 3
Viral Encephalitis
Penetrance
Nonsense Codon
Missense Mutation
Infection
Antiviral Agents
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Sancho-Shimizu, V., Pérez De Diego, R., Lorenzo, L., Halwani, R., Alangari, A., Israelsson, E., ... Casanova, J. L. (2011). Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency. Journal of Clinical Investigation, 121(12), 4889-4902. https://doi.org/10.1172/JCI59259

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

In: Journal of Clinical Investigation, Vol. 121, No. 12, 01.12.2011, p. 4889-4902.

Research output: Contribution to journalArticle

Sancho-Shimizu, V, Pérez De Diego, R, Lorenzo, L, Halwani, R, Alangari, A, Israelsson, E, Fabrega, S, Cardon, A, Maluenda, J, Tatematsu, M, Mahvelati, F, Herman, M, Ciancanelli, M, Guo, Y, AlSum, Z, Alkhamis, N, Al-Makadma, AS, Ghadiri, A, Boucherit, S, Plancoulaine, S, Picard, C, Rozenberg, F, Tardieu, M, Lebon, P, Jouanguy, E, Rezaei, N, Seya, T, Matsumoto, M, Chaussabel, DJ, Puel, A, Zhang, SY, Abel, L, Al-Muhsen, S & Casanova, JL 2011, 'Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency', Journal of Clinical Investigation, vol. 121, no. 12, pp. 4889-4902. https://doi.org/10.1172/JCI59259
Sancho-Shimizu V, Pérez De Diego R, Lorenzo L, Halwani R, Alangari A, Israelsson E et al. Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency. Journal of Clinical Investigation. 2011 Dec 1;121(12):4889-4902. https://doi.org/10.1172/JCI59259
Sancho-Shimizu, Vanessa ; Pérez De Diego, Rebeca ; Lorenzo, Lazaro ; Halwani, Rabih ; Alangari, Abdullah ; Israelsson, Elisabeth ; Fabrega, Sylvie ; Cardon, Annabelle ; Maluenda, Jerome ; Tatematsu, Megumi ; Mahvelati, Farhad ; Herman, Melina ; Ciancanelli, Michael ; Guo, Yiqi ; AlSum, Zobaida ; Alkhamis, Nouf ; Al-Makadma, Abdulkarim S. ; Ghadiri, Ata ; Boucherit, Soraya ; Plancoulaine, Sabine ; Picard, Capucine ; Rozenberg, Flore ; Tardieu, Marc ; Lebon, Pierre ; Jouanguy, Emmanuelle ; Rezaei, Nima ; Seya, Tsukasa ; Matsumoto, Misako ; Chaussabel, Damien J. ; Puel, Anne ; Zhang, Shen Ying ; Abel, Laurent ; Al-Muhsen, Saleh ; Casanova, Jean Laurent. / Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 12. pp. 4889-4902.
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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.",
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T1 - Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency

AU - Sancho-Shimizu, Vanessa

AU - Pérez De Diego, Rebeca

AU - Lorenzo, Lazaro

AU - Halwani, Rabih

AU - Alangari, Abdullah

AU - Israelsson, Elisabeth

AU - Fabrega, Sylvie

AU - Cardon, Annabelle

AU - Maluenda, Jerome

AU - Tatematsu, Megumi

AU - Mahvelati, Farhad

AU - Herman, Melina

AU - Ciancanelli, Michael

AU - Guo, Yiqi

AU - AlSum, Zobaida

AU - Alkhamis, Nouf

AU - Al-Makadma, Abdulkarim S.

AU - Ghadiri, Ata

AU - Boucherit, Soraya

AU - Plancoulaine, Sabine

AU - Picard, Capucine

AU - Rozenberg, Flore

AU - Tardieu, Marc

AU - Lebon, Pierre

AU - Jouanguy, Emmanuelle

AU - Rezaei, Nima

AU - Seya, Tsukasa

AU - Matsumoto, Misako

AU - Chaussabel, Damien J.

AU - Puel, Anne

AU - Zhang, Shen Ying

AU - Abel, Laurent

AU - Al-Muhsen, Saleh

AU - Casanova, Jean Laurent

PY - 2011/12/1

Y1 - 2011/12/1

N2 - 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.

AB - 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.

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