TLR3 controls constitutive IFN-b antiviral immunity in human fibroblasts and cortical neurons

Human herpes simplex virus-1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway resulting in impairment of central nervous system (CNS) cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism was thought to involve impaired IFN-a/b induction by the TLR3 recognition of viral dsRNA. However, we show here that human TLR3 controlled constitutive levels of IFNB mRNA and secreted bioactive IFN-b protein, thereby also constitutive mRNA levels for IFN-stimulated genes (ISGs) in fibroblasts. Tlr3-/- mouse embryonic fibroblasts also had lower basal ISG levels. Moreover, human TLR3 controlled basal levels of IFN-b secretion and ISGs mRNA in induced pluripotent stem cell-derived cortical neurons. Consistently, TLR3-deficient human fibroblasts and cortical neurons were vulnerable not only to both VSV and HSV-1, but also to several other families of viruses. The mechanism by which TLR3 restricts viral growth in human fibroblasts and cortical neurons in vitro, and by which the human central nervous system prevents infection by HSV-1 in vivo, is therefore based on the control of early viral infection by basal IFN-b immunity, rather than viral recognition triggering an amplification of IFN-a/b production.