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

TitleImpaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells.
Publication TypeJournal Article
Year of Publication2012
AuthorsLafaille FG, Pessach IM, Zhang S-Y, Ciancanelli MJ, Herman M, Abhyankar A, Ying S-W, Keros S, Goldstein PA, Mostoslavsky G, Ordovas-Montanes J, Jouanguy E, Plancoulaine S, Tu E, Elkabetz Y, Al-Muhsen S, Tardieu M, Schlaeger TM, Daley GQ, Abel L, Casanova J-L, Studer L, Notarangelo LD
Date Published2012 Nov 29
KeywordsAstrocytes, Biological Markers, Cell Differentiation, Cell Lineage, Cell Separation, Cells, Cultured, Central Nervous System, Child, Disease Susceptibility, Encephalitis, Herpes Simplex, Herpesvirus 1, Human, Humans, Immunity, Innate, Induced Pluripotent Stem Cells, Interferons, Membrane Transport Proteins, Neural Stem Cells, Neurons, Oligodendroglia, Toll-Like Receptor 3

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.

Alternate JournalNature
PubMed ID23103873
PubMed Central IDPMC3527075
Grant List1R01NS066390 / NS / NINDS NIH HHS / United States
1R03AI0883502-01 / AI / NIAID NIH HHS / United States
5R01NS072381-02 / NS / NINDS NIH HHS / United States
8UL1TR000043 / TR / NCATS NIH HHS / United States
R01 NS066390 / NS / NINDS NIH HHS / United States
R01 NS072381 / NS / NINDS NIH HHS / United States
R03 AI088352 / AI / NIAID NIH HHS / United States
UL1 TR000043 / TR / NCATS NIH HHS / United States