NEMO is a key component of NF-κB– and IRF-3–dependent TLR3-mediated immunity to herpes simplex virus Magali Audry, PhD, Michael Ciancanelli, PhD, Kun.

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Presentation transcript:

NEMO is a key component of NF-κB– and IRF-3–dependent TLR3-mediated immunity to herpes simplex virus Magali Audry, PhD, Michael Ciancanelli, PhD, Kun Yang, MD, PhD, Aurelie Cobat, MD, PhD, Huey-Hsuan Chang, PhD, Vanessa Sancho-Shimizu, PhD, Lazaro Lorenzo, Tim Niehues, MD, PhD, Janine Reichenbach, MD, Xiao-Xia Li, PhD, Alain Israel, PhD, Laurent Abel, MD, PhD, Jean-Laurent Casanova, MD, PhD, Shen-Ying Zhang, MD, PhD, Emmanuelle Jouanguy, PhD, Anne Puel, PhD Journal of Allergy and Clinical Immunology Volume 128, Issue 3, Pages 610-617.e4 (September 2011) DOI: 10.1016/j.jaci.2011.04.059 Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Induction of IFN-, IFN-, and IL-6 in response to TLR3 agonists. A, Production of IFN-, IFN-, and IL- 6 by SV40-fibroblasts from a healthy control (C), the patient (P), a patient with complete NEMO deficiency (NEMO IP), and a patient with UNC-93B deficiency (UNC-93B2/2), unstimulated or stimulated with poly(I:C) and IPH31, with or without (poly[I:C]1L and IPH311L) Lipofectamine (L), assessed by ELISA. B, Production of IFN-, IFN-, and IL-6 by SV40-fibroblasts in response to various doses of poly(I:C) for 24 hours, assessed by ELISA. Panels A and B show mean values ± SDs of 3 independent experiments. The reported P values for differences between the responses of patients and controls are for unpaired Student t tests for each experiment (∗P < .05; #P < .07). C, IFN-, IFN-, and IL-6 mRNA levels in SV40-fibroblasts left unstimulated or stimulated for 2, 4, 6, or 24 hours with poly(I:C). The panels illustrate results from 2 independent experiments performed in duplicate. Journal of Allergy and Clinical Immunology 2011 128, 610-617.e4DOI: (10.1016/j.jaci.2011.04.059) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Induction of NF-κB, IRF-3, and IRF-7 in response to poly(I:C). A, IRF-3 monomer and dimer formation in total cell extracts from healthy control (C), the patient (P), NEMO IP, and UNC-93B−/− SV40-fibroblasts, upon stimulation with poly(I:C) for 30 to 180 minutes, as assessed by Western blotting. Fold-induction of IRF-3 dimers, presented below as a histogram, was determined from the intensity of the signal on immunoblots, normalized with respect to monomer levels. B, NF-κB translocation, assessed by EMSA, in SV40-fibroblasts from a control C, the patient P, NEMO IP, and UNC-93B−/− cells, following stimulation with poly(I:C) for 1 hour and with IL1-β for 20 minutes. The panels are representative of 2 independent experiments. C, IRF-7 induction in SV40-fibroblasts after 16 hours of poly(I:C) stimulation, analyzed by Western blotting and normalized with respect to tubulin levels. This panel is representative of 3 independent experiments. Journal of Allergy and Clinical Immunology 2011 128, 610-617.e4DOI: (10.1016/j.jaci.2011.04.059) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 IFN production and cell mortality in response to viral stimulation. A, SV40-fibroblasts from a healthy control (C), the patient (P), a NEMO IP patient, and an UNC-93B−/− patient were left uninfected or infected with VSV (MOI from 0.001 to 100) for 24 hours (upper panels) or with HSV-1 (MOI from 0.0001 to 1) (lower panels) for 72 hours. The production of IFN-β (left panels) and IFN-λ (right panels) was assessed by ELISA. B, Cell mortality was estimated by lactate dehydrogenase assay, 24 hours after infection with VSV at various MOI, with (right panel) or without (left panel) prior treatment with IFN-α2b. C, The percentage of live cells was estimated by resazurin oxidation/reduction, 72 hours after infection with HSV-1, at various MOI, with (right panel) or without (left panel) prior treatment with IFN-α2b. Journal of Allergy and Clinical Immunology 2011 128, 610-617.e4DOI: (10.1016/j.jaci.2011.04.059) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Impaired responses to TLR3 in the patient’s primary fibroblasts. Production of IFN-β, IFN-λ, and IL-6 in response to stimulation with poly(I:C), or (poly(I:C)+ Lipofectamine (L) for 24 hours in primary fibroblasts from a control (C), the patient (P), and from embryonic cells from a NEMO-deficient patient (NEMO IP), as assessed by ELISA. Mean values ± SD were calculated from triplicate values for 1 experiment, representative of 3 carried out. Journal of Allergy and Clinical Immunology 2011 128, 610-617.e4DOI: (10.1016/j.jaci.2011.04.059) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Impaired responses to TLR3 in SV40-fibroblasts from patients carrying different hypomorphic mutations in NEMO. A, Production of IFN-β and IFN-λ after stimulation with poly(I:C) for 24 hours in SV40-fibroblasts from a control (C), the patient (P), other NEMO-deficient patients (P1 to P9; for whom the mutations and HSV serotypes are reported in Table E1), a NEMO IP patient, and a UNC-93B−/− patient, as assessed by ELISA. Mean values ± SD were calculated from triplicates in 1 experiment, representative of 3 carried out. B, IRF-3 monomers and dimers in total cell extracts of SV40-fibroblasts from a control (C), the patient P, a UNC-93B−/− patient, a patient with AD TLR3 deficiency (TLR3+/−), a NEMO IP patient, and 8 hypomorphic NEMO patients (P1-P8), following stimulation with poly(I:C) for 2 hours, as assessed by Western blotting. The induction of IRF-3 dimers is presented as a histogram below and was determined from the intensity of the signals on immunoblots, normalized with respect to monomer levels. Journal of Allergy and Clinical Immunology 2011 128, 610-617.e4DOI: (10.1016/j.jaci.2011.04.059) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Impaired responses to TLR3 in SV40-fibroblasts from patients carrying different hypomorphic mutations in NEMO. A, Production of IFN-β and IFN-λ after stimulation with poly(I:C) for 24 hours in SV40-fibroblasts from a control (C), the patient (P), other NEMO-deficient patients (P1 to P9; for whom the mutations and HSV serotypes are reported in Table E1), a NEMO IP patient, and a UNC-93B−/− patient, as assessed by ELISA. Mean values ± SD were calculated from triplicates in 1 experiment, representative of 3 carried out. B, IRF-3 monomers and dimers in total cell extracts of SV40-fibroblasts from a control (C), the patient P, a UNC-93B−/− patient, a patient with AD TLR3 deficiency (TLR3+/−), a NEMO IP patient, and 8 hypomorphic NEMO patients (P1-P8), following stimulation with poly(I:C) for 2 hours, as assessed by Western blotting. The induction of IRF-3 dimers is presented as a histogram below and was determined from the intensity of the signals on immunoblots, normalized with respect to monomer levels. Journal of Allergy and Clinical Immunology 2011 128, 610-617.e4DOI: (10.1016/j.jaci.2011.04.059) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions