Dataset Information

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

ABSTRACT:

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-?/?, and/or IFN-?-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-?B (NF-?B) essential modulator, which encodes the regulatory subunit of the inhibitor of the I?? kinase complex.

Methods

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.

Results

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.

Conclusion

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.

SUBMITTER: Audry M

PROVIDER: S-EPMC3164951 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Audry Magali M Ciancanelli Michael M Yang Kun K Cobat Aurelie A Chang Huey-Hsuan HH Sancho-Shimizu Vanessa V Lorenzo Lazaro L Niehues Tim T Reichenbach Janine J Li Xiao-Xia XX Israel Alain A Abel Laurent L Casanova Jean-Laurent JL Zhang Shen-Ying SY Jouanguy Emmanuelle E Puel Anne A

The Journal of allergy and clinical immunology 20110701 3

<h4>Background</h4>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-α/β, and/or IFN-λ-mediated signal transducer and activator of transcription 1-dependent immunity.<h4>Objective</h4>We explore here the molecular basis of the pathogenesis of herpes simplex encephalitis in a chil ...[more]

PMID: 21722947

Similar Datasets

Project description:ObjectiveTo determine the proportion of children with herpes simplex encephalitis (HSE) displaying TLR3 deficiency, the extent of TLR3 allelic heterogeneity, and the specific clinical features of TLR3 deficiency.MethodsWe determined the sequence of all exons of TLR3 in 110 of the 120 patients with HSE enrolled in our study who do not carry any of the previously described HSE-predisposing mutations of TLR3 pathway genes (TLR3, UNC93B1, TRIF, TRAF3, and TBK1). All the new mutant TLR3 alleles detected were characterized experimentally in-depth to establish the causal relationship between the genotype and phenotype.ResultsIn addition to the 3 previously reported TLR3-deficient patients from the same cohort, 6 other children or young adults with HSE carry 1 of 5 unique or extremely rare (minor allele frequency <0.001) missense TLR3 alleles. Two alleles (M374T, D592N) heterozygous in 3 patients are not deleterious in vitro. The other 3 are deleterious via different mechanisms: G743D+R811I and L360P heterozygous in 2 patients are loss-of-function due to low levels of expression and lack of cleavage, respectively, and R867Q homozygous in 1 patient is hypomorphic. The 3 patients' fibroblasts display impaired TLR3 responses and enhanced herpes simplex virus 1 susceptibility. Overall, TLR3 deficiency is therefore found in 6 (5%) of the 120 patients studied. There is high allelic heterogeneity, with 3 forms of autosomal dominant partial defect by negative dominance or haploinsufficiency, and 2 forms of autosomal recessive defect with complete or partial deficiency. Finally, 4 (66%) of the 6 TLR3-deficient patients had at least 1 late relapse of HSE, whereas relapse occurred in only 12 (10%) of the total cohort of 120 patients.ConclusionsChildhood-onset HSE is due to TLR3 deficiency in a traceable fraction of patients, in particular the ones with HSE recurrence. Mutations in TLR3 and TLR3 pathway genes should be searched and experimentally studied in children with HSE, and patients with proven TLR3 deficiency should be followed carefully.