title: Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells.
abstract: 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). 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.
authors.affiliation: Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, New York 10065, USA.
authors.forename: Fabien G
authors.initials: FG
authors.lastname: Lafaille
authors.forename: Itai M
authors.initials: IM
authors.lastname: Pessach
authors.forename: Shen-Ying
authors.initials: SY
authors.lastname: Zhang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ciancanelli
authors.forename: Melina
authors.initials: M
authors.lastname: Herman
authors.forename: Avinash
authors.initials: A
authors.lastname: Abhyankar
authors.forename: Shui-Wang
authors.initials: SW
authors.lastname: Ying
authors.forename: Sotirios
authors.initials: S
authors.lastname: Keros
authors.forename: Peter A
authors.initials: PA
authors.lastname: Goldstein
authors.forename: Gustavo
authors.initials: G
authors.lastname: Mostoslavsky
authors.forename: Jose
authors.initials: J
authors.lastname: Ordovas-Montanes
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Jouanguy
authors.forename: Sabine
authors.initials: S
authors.lastname: Plancoulaine
authors.forename: Edmund
authors.initials: E
authors.lastname: Tu
authors.forename: Yechiel
authors.initials: Y
authors.lastname: Elkabetz
authors.forename: Saleh
authors.initials: S
authors.lastname: Al-Muhsen
authors.forename: Marc
authors.initials: M
authors.lastname: Tardieu
authors.forename: Thorsten M
authors.initials: TM
authors.lastname: Schlaeger
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Lorenz
authors.initials: L
authors.lastname: Studer
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
mesh_terms: D001253:Astrocytes / Q000276:immunology / Q000821:virology; D015415:Biomarkers; D002454:Cell Differentiation; D019070:Cell Lineage; D002469:Cell Separation; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000276:immunology / Q000473:pathology* / Q000821:virology; D002648:Child; D004198:Disease Susceptibility; D020803:Encephalitis, Herpes Simplex / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D007113:Immunity, Innate; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000821:virology; D007372:Interferons / Q000276:immunology; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics; D058953:Neural Stem Cells / Q000276:immunology / Q000821:virology; D009474:Neurons / Q000276:immunology / Q000473:pathology / Q000821:virology; D009836:Oligodendroglia / Q000276:immunology / Q000473:pathology / Q000821:virology; D051196:Toll-Like Receptor 3 / Q000172:deficiency* / Q000235:genetics
chemical_list: D015415:Biomarkers; D026901:Membrane Transport Proteins; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; C454130:UNC93B1 protein, human; D007372:Interferons