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

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• 作者：Magali  ; Audry PhD^a ; Michael  ; Ciancanelli PhD^a ;   ; ^&lowast ; ; Kun  ; Yang MD ; PhD^b ;   ; ^c ;   ; ^&lowast ; ; Aurelie  ; Cobat MD ; PhD^b ; Huey-Hsuan  ; Chang PhD^b ; Vanessa  ; Sancho-Shimizu PhD^b ; Lazaro  ; Lorenzo^b ; Tim  ; Niehues MD ; PhD^d ; Janine  ; Reichenbach MD^e ; Xiao-Xia  ; Li PhD^f ; Alain  ; Israel PhD^g ; Laurent  ; Abel MD ; PhD^a ;   ; ^b ; Jean-Laurent  ; Casanova MD ; PhD^a ;   ; ^b ;   ; ^c ;   ; ^h ;   ; ^&Dagger ; ;   ; ^{jean-laurent.casanova@rockefeller.edu} ; Shen-Ying  ; Zhang MD ; PhD^a ;   ; ^b ;   ; ^c ;   ; ^&Dagger ; ;   ; ^{shzh289@rockefeller.edu} ; Emmanuelle  ; Jouanguy PhD^a ;   ; ^b ;   ; ^c ;   ; ^&Dagger ; ; Anne  ; Puel PhD^b ;   ; ^&Dagger ;
• 关键词：NEMO ; immunodeficiency ; Toll-like receptor 3 ; herpes simplex encephalitis
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2011
• 出版时间：September 2011
• 年：2011
• 卷：128
• 期：3
• 页码：610-617.e4
• 全文大小：1240 K
• ISSN：S009167491100844X

文摘

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-α/β, and/or IFN-λ-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-κB (NF-κB) essential modulator, which encodes the regulatory subunit of the inhibitor of the Iκβ kinase complex.

Methods

The TLR3 signaling pathway was investigated in the patient’s fibroblasts by analyses of IFN-β, IFN-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 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-β, IFN-λ, and?IL-6 production, owing to impaired activation of both NF-κB 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-β and IFN-λ 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-κB essential modulator mutations, due to?the impairment of NF-κB- and interferon regulatory factor 3-dependent-TLR3-mediated antiviral IFN production.