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: Fabien G Lafaille, Itai M Pessach, Shen-Ying Zhang, Michael J Ciancanelli, Melina Herman, Avinash Abhyankar, Shui-Wang Ying, Sotirios Keros, Peter A Goldstein, Gustavo Mostoslavsky, Jose Ordovas-Montanes, Emmanuelle Jouanguy, Sabine Plancoulaine, Edmund Tu, Yechiel Elkabetz, Saleh Al-Muhsen, Marc Tardieu, Thorsten M Schlaeger, George Q Daley, Laurent Abel, Jean-Laurent Casanova, Lorenz Studer, Luigi D Notarangelo
• Journal: Nature (Nature) Vol. 491 Issue 7426 Pg. 769-73 (Nov 29 2012) ISSN: 1476-4687 [Electronic] England
• PMID: 23103873 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Membrane Transport Proteins
• TLR3 protein, human
• Toll-Like Receptor 3
• UNC93B1 protein, human
• Interferons

Topics

• Astrocytes (immunology, virology)
• Biomarkers
• Cell Differentiation
• Cell Lineage
• Cell Separation
• Cells, Cultured
• Central Nervous System (cytology, immunology, pathology, virology)
• Child
• Disease Susceptibility
• Encephalitis, Herpes Simplex (immunology, metabolism, pathology, virology)
• Herpesvirus 1, Human (immunology, pathogenicity)
• Humans
• Immunity, Innate
• Induced Pluripotent Stem Cells (cytology, virology)
• Interferons (immunology)
• Membrane Transport Proteins (deficiency, genetics)
• Neural Stem Cells (immunology, virology)
• Neurons (immunology, pathology, virology)
• Oligodendroglia (immunology, pathology, virology)
• Toll-Like Receptor 3 (deficiency, genetics)