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Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells

In 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 i...

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Detalles Bibliográficos
Autores principales: Lafaille, Fabien G, Pessach, Itai M., Zhang, Shen-Ying, Ciancanelli, Michael J., Herman, Melina, Abhyankar, Avinash, Ying, Shui-Wang, Keros, Sotirios, Goldstein, Peter A., Mostoslavsky, Gustavo, Ordovas-Montanes, Jose, Jouanguy, Emmanuelle, Plancoulaine, Sabine, Tu, Edmund, Elkabetz, Yechiel, Al-Muhsen, Saleh, Tardieu, Marc, Schlaeger, Thorsten M., Daley, George Q., Abel, Laurent, Casanova, Jean-Laurent, Studer, Lorenz, Notarangelo, Luigi D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527075/
https://www.ncbi.nlm.nih.gov/pubmed/23103873
http://dx.doi.org/10.1038/nature11583
Descripción
Sumario:In 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.