NEMO is a key component of NF-κB- and IRF-3-dependent TLR3-mediated immunity to herpes simplex virus

Background: Children with germline mutations in Toll-like receptor 3 (TLR3), UNC93B1, TNF receptor-associated factor 3, and signal transducer and activator of transcription 1 are prone to herpes simplex virus-1 encephalitis, owing to impaired TLR3-triggered, UNC-93B-dependent, IFN-alpha/beta, and/or IFN-lambda-mediated signal transducer and activator of transcription 1-dependent immunity. Objective: We explore here the molecular basis of the pathogenesis of herpes simplex encephalitis in a child with a hypomorphic mutation in nuclear factor-kappa B (NF-kappa B) essential modulator, which encodes the regulatory subunit of the inhibitor of the I kappa b kinase complex. Methods: The TLR3 signaling pathway was investigated in the patient's fibroblasts by analyses of IFN-beta, IFN-lambda, and IL-6 mRNA and protein levels, by quantitative PCR and ELISA, respectively, upon TLR3 stimulation (TLR3 agonists or TLR3-dependent viruses). NF-kappa B activation was assessed by electrophoretic mobility shift assay and interferon regulatory factor 3 dimerization on native gels after stimulation with a TLR3 agonist. Results: The patient's fibroblasts displayed impaired responses to TLR3 stimulation in terms of IFN-beta, IFN-lambda, and IL-6 production, owing to impaired activation of both NF-kappa B and IRF-3. Moreover, vesicular stomatitis virus, a potent IFN-inducer in human fibroblasts, and herpes simplex virus-1, induced only low levels of IFN-beta and IFN-lambda in the patient's fibroblasts, resulting in enhanced viral replication and cell death, as reported for UNC-93B-deficient fibroblasts. Conclusion: Herpes simplex encephalitis may occur in patients carrying NF-kappa B essential modulator mutations, due to the impairment of NF-kappa B- and interferon regulatory factor 3-dependent-TLR3-mediated antiviral IFN production. (J Allergy Clin Immunol 2011;128:610-7.)