Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency

TLR3 is otherwise redundant in protective immunity

Yiqi Guo, Magali Audry, Michael Ciancanelli, Laia Alsina, Joana Azevedo, Melina Herman, Esperanza Anguiano, Vanessa Sancho-Shimizu, Lazaro Lorenzo, Elodie Pauwels, Paul Bastard Philippe, Rebeca Pérez de Diego, Annabelle Cardon, Guillaume Vogt, Capucine Picard, Zafitsara Zo Andrianirina, Flore Rozenberg, Pierre Lebon, Sabine Plancoulaine, Marc Tardieu & 7 others Valérie Doireau, Emmanuelle Jouanguy, Damien J. Chaussabel, Frederic Geissmann, Laurent Abel, Jean Laurent Casanova, Shen Ying Zhang

Research output: Contribution to journalArticle

152 Citations (Scopus)

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 doublestranded 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.

Original languageEnglish
Pages (from-to)2083-2098
Number of pages16
JournalJournal of Experimental Medicine
Volume208
Issue number10
DOIs
Publication statusPublished - 26 Sep 2011
Externally publishedYes

Fingerprint

Herpes Simplex Encephalitis
Human Herpesvirus 1
Simplexvirus
Immunity
Encephalitis
Poly C
Fibroblasts
Leukocytes
Central Nervous System
Infection
Viruses
Poly I-C
Virus Diseases
Dendritic Cells
Antiviral Agents
Monocytes
Blood Cells
Cell Death
Alleles
Macrophages

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency : TLR3 is otherwise redundant in protective immunity. / Guo, Yiqi; Audry, Magali; Ciancanelli, Michael; Alsina, Laia; Azevedo, Joana; Herman, Melina; Anguiano, Esperanza; Sancho-Shimizu, Vanessa; Lorenzo, Lazaro; Pauwels, Elodie; Philippe, Paul Bastard; de Diego, Rebeca Pérez; Cardon, Annabelle; Vogt, Guillaume; Picard, Capucine; Andrianirina, Zafitsara Zo; Rozenberg, Flore; Lebon, Pierre; Plancoulaine, Sabine; Tardieu, Marc; Doireau, Valérie; Jouanguy, Emmanuelle; Chaussabel, Damien J.; Geissmann, Frederic; Abel, Laurent; Casanova, Jean Laurent; Zhang, Shen Ying.

In: Journal of Experimental Medicine, Vol. 208, No. 10, 26.09.2011, p. 2083-2098.

Research output: Contribution to journalArticle

Guo, Y, Audry, M, Ciancanelli, M, Alsina, L, Azevedo, J, Herman, M, Anguiano, E, Sancho-Shimizu, V, Lorenzo, L, Pauwels, E, Philippe, PB, de Diego, RP, Cardon, A, Vogt, G, Picard, C, Andrianirina, ZZ, Rozenberg, F, Lebon, P, Plancoulaine, S, Tardieu, M, Doireau, V, Jouanguy, E, Chaussabel, DJ, Geissmann, F, Abel, L, Casanova, JL & Zhang, SY 2011, 'Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity', Journal of Experimental Medicine, vol. 208, no. 10, pp. 2083-2098. https://doi.org/10.1084/jem.20101568
Guo, Yiqi ; Audry, Magali ; Ciancanelli, Michael ; Alsina, Laia ; Azevedo, Joana ; Herman, Melina ; Anguiano, Esperanza ; Sancho-Shimizu, Vanessa ; Lorenzo, Lazaro ; Pauwels, Elodie ; Philippe, Paul Bastard ; de Diego, Rebeca Pérez ; Cardon, Annabelle ; Vogt, Guillaume ; Picard, Capucine ; Andrianirina, Zafitsara Zo ; Rozenberg, Flore ; Lebon, Pierre ; Plancoulaine, Sabine ; Tardieu, Marc ; Doireau, Valérie ; Jouanguy, Emmanuelle ; Chaussabel, Damien J. ; Geissmann, Frederic ; Abel, Laurent ; Casanova, Jean Laurent ; Zhang, Shen Ying. / Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency : TLR3 is otherwise redundant in protective immunity. In: Journal of Experimental Medicine. 2011 ; Vol. 208, No. 10. pp. 2083-2098.
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AU - Ciancanelli, Michael

AU - Alsina, Laia

AU - Azevedo, Joana

AU - Herman, Melina

AU - Anguiano, Esperanza

AU - Sancho-Shimizu, Vanessa

AU - Lorenzo, Lazaro

AU - Pauwels, Elodie

AU - Philippe, Paul Bastard

AU - de Diego, Rebeca Pérez

AU - Cardon, Annabelle

AU - Vogt, Guillaume

AU - Picard, Capucine

AU - Andrianirina, Zafitsara Zo

AU - Rozenberg, Flore

AU - Lebon, Pierre

AU - Plancoulaine, Sabine

AU - Tardieu, Marc

AU - Doireau, Valérie

AU - Jouanguy, Emmanuelle

AU - Chaussabel, Damien J.

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