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

Article

关键词: HERPES-SIMPLEX ENCEPHALITIS;    EMBRYONIC STEM-CELLS;    TOLL-LIKE RECEPTOR-3;    RETICULAR THALAMIC NEURONS;    CENTRAL-NERVOUS-SYSTEM;    DOUBLE-STRANDED-RNA;    TLR3 DEFICIENCY;    HUMAN ES;    PROTECTIVE IMMUNITY;    VIRUS ENCEPHALITIS;   

DOI  :  10.1038/nature11583

来源: SCIE

【 摘 要 】

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)(1-3). 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-beta (IFN-beta) and/or IFN-lambda 1 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-beta and IFN-lambda 1 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-alpha or IFN-beta (IFN-alpha/beta) but not IFN-lambda 1. Thus, impaired TLR3- and UNC-93B-dependent IFN-alpha/beta 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.

【 授权许可】

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