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



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-?/?, and/or IFN-?-mediated signal transducer and activator of transcription 1-dependent immunity.


We explore here the molecular basis of the pathogenesis of herpes simplex encephalitis in a child with a hypomorphic mutation in nuclear factor-?B (NF-?B) essential modulator, which encodes the regulatory subunit of the inhibitor of the I?? kinase complex.


The TLR3 signaling pathway was investigated in the patient's fibroblasts by analyses of IFN-?, IFN-?, and IL-6 mRNA and protein levels, by quantitative PCR and ELISA, respectively, upon TLR3 stimulation (TLR3 agonists or TLR3-dependent viruses). NF-?B activation was assessed by electrophoretic mobility shift assay and interferon regulatory factor 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-?, IFN-?, and IL-6 production, owing to impaired activation of both NF-?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-? and IFN-? in the patient's fibroblasts, resulting in enhanced viral replication and cell death, as reported for UNC-93B-deficient fibroblasts.


Herpes simplex encephalitis may occur in patients carrying NF-?B essential modulator mutations, due to the impairment of NF-?B- and interferon regulatory factor 3-dependent-TLR3-mediated antiviral IFN production.

PROVIDER: S-EPMC3164951 | BioStudies |

REPOSITORIES: biostudies

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