Lafaille, Fabien GPessach, Itai M.Zhang, Shen-YingCiancanelli, Michael J.Herman, MelinaAbhyankar, AvinashYing, Shui-WangKeros, SotiriosGoldstein, Peter A.Mostoslavsky, GustavoOrdovas-Montanes, JoseJouanguy, EmmanuellePlancoulaine, SabineTu, EdmundElkabetz, YechielAl-Muhsen, SalehTardieu, MarcSchlaeger, ThorstenDaley, GeorgeAbel, LaurentCasanova, Jean-LaurentStuder, LorenzNotarangelo, Luigi2013-10-162012Lafaille, Fabien G, Itai M. Pessach, Shen-Ying Zhang, Michael J. Ciancanelli, Melina Herman, Avinash Abhyankar, Shui-Wang Ying, et al. 2012. Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells. Nature 491(7426): 769-773.0028-0836http://nrs.harvard.edu/urn-3:HUL.InstRepos:11177949In the course of primary infection with herpes simplex virus 1 (HSV-1), children with inborn errors of TLR3 immunity are prone to HSV-1 encephalitis (HSE) 1–3. We tested the hypothesis that the pathogenesis of HSE involves non hematopoietic central nervous system (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 IFN-β and/or IFN-γ1 in response to poly(I:C) stimulation was dependent on TLR3 and UNC-93B in all cells tested. However, the induction of IFN-β and IFN-γ1 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 demonstrated that the genetic defect was the cause of the poly(I:C) and HSV-1 phenotypes. The viral infection phenotype was further rescued by treatment with exogenous IFN-α/β, but not IFN-γ1.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.en-USJournal Article2013-10-1610.1038/nature11583