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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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.
The authors declare no competing financial interests.
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Lafaille, F., Pessach, I., Zhang, S. et al. Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells. Nature 491, 769–773 (2012). https://doi.org/10.1038/nature11583
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