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 TardieuValérie Doireau, Emmanuelle Jouanguy, Damien J. Chaussabel, Frederic Geissmann, Laurent Abel, Jean Laurent Casanova, Shen Ying Zhang

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168 Citations (Scopus)


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
Issue number10
Publication statusPublished - 26 Sep 2011
Externally publishedYes


ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Guo, Y., Audry, M., Ciancanelli, M., Alsina, L., Azevedo, J., Herman, M., Anguiano, E., Sancho-Shimizu, V., Lorenzo, L., Pauwels, E., Philippe, P. B., de Diego, R. P., Cardon, A., Vogt, G., Picard, C., Andrianirina, Z. Z., Rozenberg, F., Lebon, P., Plancoulaine, S., ... Zhang, S. Y. (2011). Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity. Journal of Experimental Medicine, 208(10), 2083-2098. https://doi.org/10.1084/jem.20101568