Children with germline mutations in TLR3, UNC93B1, TRAF3 and STAT1 are prone to herpes simplex virus-1 (HSV-1) encephalitis (HSE), owing to impaired TLR3-triggered, UNC-93B-dependent, interferon (IFN)-α/β and/or -λ-mediated STAT1-dependent immunity.
We explore here the molecular basis of the pathogenesis of HSE in a child with a hypomorphic mutation in NEMO, which encodes the regulatory subunit of the IκB kinase (IKK) complex.
The TLR3 signaling pathway was investigated in the patient's fibroblasts by analyses of IFN-β, -λ, and IL-6 mRNA and protein levels, by quantitative PCR and ELISA, respectively, upon TLR3 stimulation (TLR3 agonists or TLR3-dependent viruses). NF-κB activation was assessed by EMSA and IRF-3 dimerization on native gels after stimulation with a TLR3 agonist.
The patient's fibroblasts displayed impaired responses to TLR3 stimulation in terms of IFN-β, -λ, and IL-6 production, owing to impaired activation of both NF-κB and IRF-3. Moreover, vesicular stomatitis virus (VSV), a potent IFN-inducer in human fibroblasts, and HSV-1, induced only low levels of IFN-β and -λ in the patient's fibroblasts, resulting in enhanced viral replication and cell death, as reported for UNC-93B-deficient fibroblasts.
HSE may occur in patients carrying NEMO mutations, due to the impairment of NF-κB- and IRF-3-dependent-TLR3-mediated antiviral IFN production.