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In the course of primary infection with herpes simplex virus 1 (HSV-1), children with inborn errors of toll-like receptor 3 (TLR3) immunity are prone to HSV-1 encephalitis (HSE)1,2,3. We tested the hypothesis that the pathogenesis of HSE involves non-haematopoietic CNS-resident cells. We derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3- and UNC-93B-deficient patients and from controls. These iPSCs were differentiated into highly purified populations of neural stem cells (NSCs), neurons, astrocytes and oligodendrocytes. The induction of interferon-β (IFN-β) and/or IFN-λ1 in response to stimulation by the dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) was dependent on TLR3 and UNC-93B in all cells tested. However, the induction of IFN-β and IFN-λ1 in response to HSV-1 infection was impaired selectively in UNC-93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC-93B-deficient NSCs and astrocytes were not. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection. The rescue of UNC-93B- and TLR3-deficient cells with the corresponding wild-type allele showed that the genetic defect was the cause of the poly(I:C) and HSV-1 phenotypes. The viral infection phenotype was rescued further by treatment with exogenous IFN-α or IFN-β ( IFN-α/β) but not IFN-λ1. Thus, impaired TLR3- and UNC-93B-dependent IFN-α/β intrinsic immunity to HSV-1 in the CNS, in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3-pathway deficiencies.

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Change history

  • 28 November 2012

    Minor typographical corrections were made to Figs 1a and 3e.


Primary accessions

Gene Expression Omnibus

Data deposits

The transcriptome data have been deposited in the Gene Expression Omnibus database under accession number GSE40593.


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We thank our patients, their families and physicians; and the members of the three laboratories for helpful discussions and critical reading of this manuscript. The work was funded by grant number 8UL1TR000043 from the National Center for Translational Sciences (NCATS), the National Institutes of Health (NIH), the Rockefeller University, the St. Giles Foundation, the ANR, INSERM, Paris Descartes University, the March of Dimes, NIH grant 5R01NS072381-02 (to J.-L.C., L.S. and L.D.N.), NIH grant 1R03AI0883502-01 (to L.D.N.), NIH grant 1R01NS066390 and the Manton Foundation, the Israeli Centers of Research Excellence (I-CORE), and Gene Regulation in Complex Human Disease, Center No 41/11 (to I.M.P.). F.G.L. is supported by the New York Stem Cell Foundation.

Author information

Author notes

    • Fabien G. Lafaille
    • , Itai M. Pessach
    •  & Shen-Ying Zhang

    These authors contributed equally to this work.


  1. Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, New York 10065, USA

    • Fabien G. Lafaille
    • , Edmund Tu
    •  & Lorenz Studer
  2. Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, New York 10065, USA

    • Fabien G. Lafaille
    • , Edmund Tu
    •  & Lorenz Studer
  3. Division of Immunology, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Itai M. Pessach
    • , Jose Ordovas-Montanes
    •  & Luigi D. Notarangelo
  4. The Talpiot Medical Leadership Program, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 52621, Israel

    • Itai M. Pessach
  5. St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, New York 10065, USA

    • Shen-Ying Zhang
    • , Michael J. Ciancanelli
    • , Melina Herman
    • , Avinash Abhyankar
    • , Emmanuelle Jouanguy
    • , Laurent Abel
    •  & Jean-Laurent Casanova
  6. Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, University Paris Descartes, Necker Medical School, U980, Paris 75015, France

    • Shen-Ying Zhang
    • , Melina Herman
    • , Emmanuelle Jouanguy
    • , Sabine Plancoulaine
    • , Laurent Abel
    •  & Jean-Laurent Casanova
  7. C.V. Starr Laboratory for Molecular Neuropharmacology, Department of Anesthesiology, Weill Cornell Medical College, New York, New York 10065, USA

    • Shui-Wang Ying
    •  & Peter A. Goldstein
  8. Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medical College, New York, New York 10065, USA

    • Sotirios Keros
  9. Section of Gastroenterology, Department of Medicine and Center for Regenerative Medicine (CReM), Boston University School of Medicine, Boston, Massachusetts 02118, USA

    • Gustavo Mostoslavsky
  10. Laboratory for Pluripotent and Neural Stem Cell Biology, Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

    • Yechiel Elkabetz
  11. Prince Naif Center for Immunology Research, Department of Pediatrics, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia

    • Saleh Al-Muhsen
  12. Department of Pediatric Neurology, Assistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Kremlin-Bicêtre, 94275, France

    • Marc Tardieu
  13. Division of Pediatric Hematology/Oncology, Children's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA

    • Thorsten M. Schlaeger
    •  & George Q. Daley
  14. Pediatric Hematology-Immunology Unit, Necker Hospital, Paris 75015, France

    • Jean-Laurent Casanova
  15. The Manton Center for Orphan Disease Research, Children’s Hospital, Boston, Massachusetts 02115, USA

    • Luigi D. Notarangelo


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F.G.L., I.M.P., S.-Y.Z., J.-L.C., L.S. and L.D.N. designed the experiments. F.G.L., I.M.P., S.-Y.Z., M.J.C., M.H., A. A., G.M., S.-W.Y., S.K., P.A.G, J.O.-M., E.J., E.T., Y.E. and T.M.S. carried out the experiments. S.A. and M.T. helped to obtain materials from patients and interpret the findings. G.Q.D. and L.A. helped to analyse and describe the data. S.-Y.Z. and J.-L.C. wrote the manuscript with the aid of F.G.L., I.M.P., L.S. and L.D.N. F.G.L., I.M.P. and S.-Y. Zhang are equal first authors. J.L.C., L.S. and L.D.N. are co-senior authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Shen-Ying Zhang or Jean-Laurent Casanova.

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