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dc.contributor.authorLafaille, Fabien G
dc.contributor.authorPessach, Itai M.
dc.contributor.authorZhang, Shen-Ying
dc.contributor.authorCiancanelli, Michael J.
dc.contributor.authorHerman, Melina
dc.contributor.authorAbhyankar, Avinash
dc.contributor.authorYing, Shui-Wang
dc.contributor.authorKeros, Sotirios
dc.contributor.authorGoldstein, Peter A.
dc.contributor.authorMostoslavsky, Gustavo
dc.contributor.authorOrdovas-Montanes, Jose Manuel
dc.contributor.authorJouanguy, Emmanuelle
dc.contributor.authorPlancoulaine, Sabine
dc.contributor.authorTu, Edmund
dc.contributor.authorElkabetz, Yechiel
dc.contributor.authorAl-Muhsen, Saleh
dc.contributor.authorTardieu, Marc
dc.contributor.authorSchlaeger, Thorsten M.
dc.contributor.authorDaley, George Quentin
dc.contributor.authorAbel, Laurent
dc.contributor.authorCasanova, Jean-Laurent
dc.contributor.authorStuder, Lorenz
dc.contributor.authorNotarangelo, Luigi D.
dc.date.accessioned2013-10-16T15:18:08Z
dc.date.issued2012
dc.identifier.citationLafaille, 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.en_US
dc.identifier.issn0028-0836en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:11177949
dc.description.abstractIn 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_US
dc.language.isoen_USen_US
dc.relation.isversionofdoi:10.1038/nature11583en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527075/pdf/en_US
dash.licenseLAA
dc.titleImpaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cellsen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalNatureen_US
dash.depositing.authorNotarangelo, Luigi D.
dc.date.available2013-10-16T15:18:08Z
dc.identifier.doi10.1038/nature11583*
dash.authorsorderedfalse
dash.contributor.affiliatedOrdovas-Montanes, Jose
dash.contributor.affiliatedSchlaeger, Thorsten
dash.contributor.affiliatedNotarangelo, Luigi
dash.contributor.affiliatedDaley, George
dc.identifier.orcid0000-0001-5444-5601


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