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

TLDR: 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 TLR 3-pathway deficiencies.

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) 1–3 .W e tested the hypothesis that the pathogenesis of HSE involves nonhaematopoietic 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-b (IFN-b) and/or IFN-l1 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-b and IFN-l1 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 TLR3deficient 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-a or IFN-b ( IFN-a/b) but not IFN-l1. Thus, impaired TLR3- and UNC-93B-dependent IFN-a/b 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. Childhood HSE is a rare, life-threatening, central nervous system (CNS)-restricted complication of primary infection with HSV-1, an almost ubiquitous virus that is typically innocuous 4 . Children with HSE are not unusually susceptible to other infectious agents, including viruses, or even to HSV-1-related diseases affecting sites other than the CNS 4,5 . HSV-1 reaches the CNS from the oral and nasal epithelium, via the cranial nerves 4 . We identified autosomal recessive UNC-93B deficiency as the first genetic aetiology of childhood HSE 1 . UNC-93B is required for TLR3, TLR7, TLR8 and TLR9 responses 1,6 . We then identified autosomal-recessive or autosomal-dominant deficiencies of TLR3 (refs 2 and 3), TRAF3 (ref. 7), TRIF 8 and TBK1 (ref. 9), revealing