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

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Author
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
Jouanguy, Emmanuelle
Plancoulaine, Sabine
Tu, Edmund
Elkabetz, Yechiel
Al-Muhsen, Saleh
Tardieu, Marc
Abel, Laurent
Casanova, Jean-Laurent
Studer, Lorenz
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/nature11583Metadata
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Lafaille, 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.Abstract
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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527075/pdf/Terms of Use
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