Details

Autor(en) / Beteiligte

• LAFAILLE, Fabien G
• PESSACH, Itai M
• ORDOVAS-MONTANES, Jose
• JOUANGUY, Emmanuelle
• PLANCOULAINE, Sabine
• TU, Edmund
• ELKABETZ, Yechiel
• AL-MUHSEN, Saleh
• TARDIEU, Marc
• SCHLAEGER, Thorsten M
• DALEY, George Q
• ABEL, Laurent
• ZHANG, Shen-Ying
• CASANOVA, Jean-Laurent
• STUDER, Lorenz
• NOTARANGELO, Luigi D
• CIANCANELLI, Michael J
• MERMAN, Melina
• ABHYANKAR, Avinash
• YING, Shui-Wang
• KEROS, Sotirios
• GOLDSTEIN, Peter A
• MOSTOSLAVSKY, Gustavo

Titel

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

Ist Teil von

• Nature (London), 2012-11, Vol.491 (7426), p.769-773

Ort / Verlag

London: Nature Publishing Group

Erscheinungsjahr

2012

Quelle

Psychology and Behavioral Sciences Collection

Beschreibungen/Notizen

• 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.