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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">NEMO is a key component of NF-κB- and IRF-3-dependent TLR3-mediated immunity to herpes simplex virus</title><author><name sortKey="Audry, Magali" sort="Audry, Magali" uniqKey="Audry M" first="Magali" last="Audry">Magali Audry</name><affiliation><nlm:aff id="A1"> St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation></author><author><name sortKey="Ciancanelli, Michael" sort="Ciancanelli, Michael" uniqKey="Ciancanelli M" first="Michael" last="Ciancanelli">Michael Ciancanelli</name><affiliation><nlm:aff id="A1"> St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation></author><author><name sortKey="Yang, Kun" sort="Yang, Kun" uniqKey="Yang K" first="Kun" last="Yang">Kun Yang</name><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> French-Chinese Laboratory of Genomics and Life Sciences, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.</nlm:aff></affiliation></author><author><name sortKey="Cobat, Aurelie" sort="Cobat, Aurelie" uniqKey="Cobat A" first="Aurelie" last="Cobat">Aurelie Cobat</name><affiliation><nlm:aff id="A1"> St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation></author><author><name sortKey="Chang, Huey Hsuan" sort="Chang, Huey Hsuan" uniqKey="Chang H" first="Huey-Hsuan" last="Chang">Huey-Hsuan Chang</name><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation></author><author><name sortKey="Sancho Shimizu, Vanessa" sort="Sancho Shimizu, Vanessa" uniqKey="Sancho Shimizu V" first="Vanessa" last="Sancho-Shimizu">Vanessa Sancho-Shimizu</name><affiliation><nlm:aff id="A1"> St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation></author><author><name sortKey="Lorenzo, Lazaro" sort="Lorenzo, Lazaro" uniqKey="Lorenzo L" first="Lazaro" last="Lorenzo">Lazaro Lorenzo</name><affiliation><nlm:aff id="A1"> St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation></author><author><name sortKey="Niehues, Tim" sort="Niehues, Tim" uniqKey="Niehues T" first="Tim" last="Niehues">Tim Niehues</name><affiliation><nlm:aff id="A4"> Department of Pediatric Oncology, Hematology and Immunology, Pediatric Immunology and Rheumatology, Centre for Child Health, Heinrich-Heine-University, Dusseldorf D-40225, Germany, EU.</nlm:aff></affiliation></author><author><name sortKey="Reichenbach, Janine" sort="Reichenbach, Janine" uniqKey="Reichenbach J" first="Janine" last="Reichenbach">Janine Reichenbach</name><affiliation><nlm:aff id="A5"> Division of Immunology, Hematology, and Bone Marrow Transplantation, University Children's Hospital, Zurich, Switzerland.</nlm:aff></affiliation></author><author><name sortKey="Li, Xiao Xia" sort="Li, Xiao Xia" uniqKey="Li X" first="Xiao-Xia" last="Li">Xiao-Xia Li</name><affiliation><nlm:aff id="A6"> Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.</nlm:aff></affiliation></author><author><name sortKey="Israel, Alain" sort="Israel, Alain" uniqKey="Israel A" first="Alain" last="Israel">Alain Israel</name><affiliation><nlm:aff id="A7"> Molecular Signaling and Cellular Activation Unit, URA 2582 CNRS Institut Pasteur, Paris 75015, France, EU.</nlm:aff></affiliation></author><author><name sortKey="Abel, Laurent" sort="Abel, Laurent" uniqKey="Abel L" first="Laurent" last="Abel">Laurent Abel</name><affiliation><nlm:aff id="A1"> St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation></author><author><name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name><affiliation><nlm:aff id="A1"> St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> French-Chinese Laboratory of Genomics and Life Sciences, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.</nlm:aff></affiliation><affiliation><nlm:aff id="A8"> Pediatric Immunology-Hematology Unit, Necker Hospital for Sick Children, Paris 75015, France, EU.</nlm:aff></affiliation></author><author><name sortKey="Zhang, Shen Ying" sort="Zhang, Shen Ying" uniqKey="Zhang S" first="Shen-Ying" last="Zhang">Shen-Ying Zhang</name><affiliation><nlm:aff id="A1"> St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> French-Chinese Laboratory of Genomics and Life Sciences, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.</nlm:aff></affiliation></author><author><name sortKey="Jouanguy, Emmanuelle" sort="Jouanguy, Emmanuelle" uniqKey="Jouanguy E" first="Emmanuelle" last="Jouanguy">Emmanuelle Jouanguy</name><affiliation><nlm:aff id="A1"> St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> French-Chinese Laboratory of Genomics and Life Sciences, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.</nlm:aff></affiliation></author><author><name sortKey="Puel, Anne" sort="Puel, Anne" uniqKey="Puel A" first="Anne" last="Puel">Anne Puel</name><affiliation><nlm:aff id="A1"> St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">21722947</idno><idno type="pmc">3164951</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164951</idno><idno type="RBID">PMC:3164951</idno><idno type="doi">10.1016/j.jaci.2011.04.059</idno><date when="2011">2011</date><idno type="wicri:Area/Pmc/Corpus">002996</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002996</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">NEMO is a key component of NF-κB- and IRF-3-dependent TLR3-mediated immunity to herpes simplex virus</title><author><name sortKey="Audry, Magali" sort="Audry, Magali" uniqKey="Audry M" first="Magali" last="Audry">Magali Audry</name><affiliation><nlm:aff id="A1"> St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation></author><author><name sortKey="Ciancanelli, Michael" sort="Ciancanelli, Michael" uniqKey="Ciancanelli M" first="Michael" last="Ciancanelli">Michael Ciancanelli</name><affiliation><nlm:aff id="A1"> St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation></author><author><name sortKey="Yang, Kun" sort="Yang, Kun" uniqKey="Yang K" first="Kun" last="Yang">Kun Yang</name><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> French-Chinese Laboratory of Genomics and Life Sciences, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.</nlm:aff></affiliation></author><author><name sortKey="Cobat, Aurelie" sort="Cobat, Aurelie" uniqKey="Cobat A" first="Aurelie" last="Cobat">Aurelie Cobat</name><affiliation><nlm:aff id="A1"> St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation></author><author><name sortKey="Chang, Huey Hsuan" sort="Chang, Huey Hsuan" uniqKey="Chang H" first="Huey-Hsuan" last="Chang">Huey-Hsuan Chang</name><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation></author><author><name sortKey="Sancho Shimizu, Vanessa" sort="Sancho Shimizu, Vanessa" uniqKey="Sancho Shimizu V" first="Vanessa" last="Sancho-Shimizu">Vanessa Sancho-Shimizu</name><affiliation><nlm:aff id="A1"> St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation></author><author><name sortKey="Lorenzo, Lazaro" sort="Lorenzo, Lazaro" uniqKey="Lorenzo L" first="Lazaro" last="Lorenzo">Lazaro Lorenzo</name><affiliation><nlm:aff id="A1"> St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation></author><author><name sortKey="Niehues, Tim" sort="Niehues, Tim" uniqKey="Niehues T" first="Tim" last="Niehues">Tim Niehues</name><affiliation><nlm:aff id="A4"> Department of Pediatric Oncology, Hematology and Immunology, Pediatric Immunology and Rheumatology, Centre for Child Health, Heinrich-Heine-University, Dusseldorf D-40225, Germany, EU.</nlm:aff></affiliation></author><author><name sortKey="Reichenbach, Janine" sort="Reichenbach, Janine" uniqKey="Reichenbach J" first="Janine" last="Reichenbach">Janine Reichenbach</name><affiliation><nlm:aff id="A5"> Division of Immunology, Hematology, and Bone Marrow Transplantation, University Children's Hospital, Zurich, Switzerland.</nlm:aff></affiliation></author><author><name sortKey="Li, Xiao Xia" sort="Li, Xiao Xia" uniqKey="Li X" first="Xiao-Xia" last="Li">Xiao-Xia Li</name><affiliation><nlm:aff id="A6"> Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.</nlm:aff></affiliation></author><author><name sortKey="Israel, Alain" sort="Israel, Alain" uniqKey="Israel A" first="Alain" last="Israel">Alain Israel</name><affiliation><nlm:aff id="A7"> Molecular Signaling and Cellular Activation Unit, URA 2582 CNRS Institut Pasteur, Paris 75015, France, EU.</nlm:aff></affiliation></author><author><name sortKey="Abel, Laurent" sort="Abel, Laurent" uniqKey="Abel L" first="Laurent" last="Abel">Laurent Abel</name><affiliation><nlm:aff id="A1"> St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation></author><author><name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name><affiliation><nlm:aff id="A1"> St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> French-Chinese Laboratory of Genomics and Life Sciences, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.</nlm:aff></affiliation><affiliation><nlm:aff id="A8"> Pediatric Immunology-Hematology Unit, Necker Hospital for Sick Children, Paris 75015, France, EU.</nlm:aff></affiliation></author><author><name sortKey="Zhang, Shen Ying" sort="Zhang, Shen Ying" uniqKey="Zhang S" first="Shen-Ying" last="Zhang">Shen-Ying Zhang</name><affiliation><nlm:aff id="A1"> St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> French-Chinese Laboratory of Genomics and Life Sciences, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.</nlm:aff></affiliation></author><author><name sortKey="Jouanguy, Emmanuelle" sort="Jouanguy, Emmanuelle" uniqKey="Jouanguy E" first="Emmanuelle" last="Jouanguy">Emmanuelle Jouanguy</name><affiliation><nlm:aff id="A1"> St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> French-Chinese Laboratory of Genomics and Life Sciences, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.</nlm:aff></affiliation></author><author><name sortKey="Puel, Anne" sort="Puel, Anne" uniqKey="Puel A" first="Anne" last="Puel">Anne Puel</name><affiliation><nlm:aff id="A1"> St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="A2"> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</nlm:aff></affiliation></author></analytic><series><title level="j">The Journal of allergy and clinical immunology</title><idno type="ISSN">0091-6749</idno><idno type="eISSN">1097-6825</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="S1"><title>Background</title><p id="P3">Children with germline mutations in <italic>TLR3, UNC93B1, TRAF3</italic> and <italic>STAT1</italic> are prone to herpes simplex virus-1 (HSV-1) encephalitis (HSE), owing to impaired TLR3-triggered, UNC-93B-dependent, interferon (IFN)-α/β and/or -λ-mediated STAT1-dependent immunity.</p></sec><sec id="S2"><title>Objective</title><p id="P4">We explore here the molecular basis of the pathogenesis of HSE in a child with a hypomorphic mutation in <italic>NEMO</italic>, which encodes the regulatory subunit of the IκB kinase (IKK) complex.</p></sec><sec sec-type="methods" id="S3"><title>Methods</title><p id="P5">The TLR3 signaling pathway was investigated in the patient's fibroblasts by analyses of IFN-β, -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 EMSA and IRF-3 dimerization on native gels after stimulation with a TLR3 agonist.</p></sec><sec id="S4"><title>Results</title><p id="P6">The patient's fibroblasts displayed impaired responses to TLR3 stimulation in terms of IFN-β, -λ, and IL-6 production, owing to impaired activation of both NF-κB and IRF-3. Moreover, vesicular stomatitis virus (VSV), a potent IFN-inducer in human fibroblasts, and HSV-1, induced only low levels of IFN-β and -λ in the patient's fibroblasts, resulting in enhanced viral replication and cell death, as reported for UNC-93B-deficient fibroblasts.</p></sec><sec id="S5"><title>Conclusion</title><p id="P7">HSE may occur in patients carrying <italic>NEMO</italic> mutations, due to the impairment of NF-κB- and IRF-3-dependent-TLR3-mediated antiviral IFN production.</p></sec></div></front></TEI><pmc article-type="research-article" xml:lang="en"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">1275002</journal-id><journal-id journal-id-type="pubmed-jr-id">4431</journal-id><journal-id journal-id-type="nlm-ta">J Allergy Clin Immunol</journal-id><journal-title-group><journal-title>The Journal of allergy and clinical immunology</journal-title></journal-title-group><issn pub-type="ppub">0091-6749</issn><issn pub-type="epub">1097-6825</issn></journal-meta><article-meta><article-id pub-id-type="pmid">21722947</article-id><article-id pub-id-type="pmc">3164951</article-id><article-id pub-id-type="doi">10.1016/j.jaci.2011.04.059</article-id><article-id pub-id-type="manuscript">NIHMS300109</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>NEMO is a key component of NF-κB- and IRF-3-dependent TLR3-mediated immunity to herpes simplex virus</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Audry</surname><given-names>Magali</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Ciancanelli</surname><given-names>Michael</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref><xref ref-type="author-notes" rid="FN2">*</xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Kun</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A3">3</xref><xref ref-type="author-notes" rid="FN2">*</xref></contrib><contrib contrib-type="author"><name><surname>Cobat</surname><given-names>Aurelie</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Chang</surname><given-names>Huey-Hsuan</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Sancho-Shimizu</surname><given-names>Vanessa</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Lorenzo</surname><given-names>Lazaro</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Niehues</surname><given-names>Tim</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Reichenbach</surname><given-names>Janine</given-names></name><degrees>MD</degrees><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Xiao-Xia</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Israel</surname><given-names>Alain</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Abel</surname><given-names>Laurent</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Casanova</surname><given-names>Jean-Laurent</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A3">3</xref><xref ref-type="aff" rid="A8">8</xref><xref ref-type="author-notes" rid="FN3">**</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Shen-Ying</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A3">3</xref><xref ref-type="author-notes" rid="FN3">**</xref></contrib><contrib contrib-type="author"><name><surname>Jouanguy</surname><given-names>Emmanuelle</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A3">3</xref><xref ref-type="author-notes" rid="FN3">**</xref></contrib><contrib contrib-type="author"><name><surname>Puel</surname><given-names>Anne</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref><xref ref-type="author-notes" rid="FN3">**</xref></contrib></contrib-group><aff id="A1"><label>1</label> St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA.</aff><aff id="A2"><label>2</label> Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, INSERM U980, University Paris Descartes, Necker Medical School, Paris, 75015 France, EU.</aff><aff id="A3"><label>3</label> French-Chinese Laboratory of Genomics and Life Sciences, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.</aff><aff id="A4"><label>4</label> Department of Pediatric Oncology, Hematology and Immunology, Pediatric Immunology and Rheumatology, Centre for Child Health, Heinrich-Heine-University, Dusseldorf D-40225, Germany, EU.</aff><aff id="A5"><label>5</label> Division of Immunology, Hematology, and Bone Marrow Transplantation, University Children's Hospital, Zurich, Switzerland.</aff><aff id="A6"><label>6</label> Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.</aff><aff id="A7"><label>7</label> Molecular Signaling and Cellular Activation Unit, URA 2582 CNRS Institut Pasteur, Paris 75015, France, EU.</aff><aff id="A8"><label>8</label> Pediatric Immunology-Hematology Unit, Necker Hospital for Sick Children, Paris 75015, France, EU.</aff><author-notes><corresp id="CR1">Address correspondence to Jean-Laurent Casanova, MD, PhD (<email>jean-laurent.casanova@rockefeller.edu</email>) or Shen-Ying Zhang, MD, PhD (<email>shzh289@rockefeller.edu</email>) St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, 10065 NY, USA. Tel: 1 212 327 7332, Fax: 1 212 327 7330</corresp><fn fn-type="equal" id="FN2"><label>*</label><p id="P1">contributed equally to this study.</p></fn><fn fn-type="equal" id="FN3"><label>**</label><p id="P2">contributed equally to this study.</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>31</day><month>5</month><year>2011</year></pub-date><pub-date pub-type="epub"><day>1</day><month>7</month><year>2011</year></pub-date><pub-date pub-type="ppub"><month>9</month><year>2011</year></pub-date><pub-date pub-type="pmc-release"><day>1</day><month>9</month><year>2012</year></pub-date><volume>128</volume><issue>3</issue><fpage>610</fpage><lpage>617.e4</lpage><permissions><copyright-statement>© 2011 American Academy of Allergy, Asthma and Immunology. Published by Mosby, Inc. All rights reserved.</copyright-statement><copyright-year>2011</copyright-year></permissions><abstract><sec id="S1"><title>Background</title><p id="P3">Children with germline mutations in <italic>TLR3, UNC93B1, TRAF3</italic> and <italic>STAT1</italic> are prone to herpes simplex virus-1 (HSV-1) encephalitis (HSE), owing to impaired TLR3-triggered, UNC-93B-dependent, interferon (IFN)-α/β and/or -λ-mediated STAT1-dependent immunity.</p></sec><sec id="S2"><title>Objective</title><p id="P4">We explore here the molecular basis of the pathogenesis of HSE in a child with a hypomorphic mutation in <italic>NEMO</italic>, which encodes the regulatory subunit of the IκB kinase (IKK) complex.</p></sec><sec sec-type="methods" id="S3"><title>Methods</title><p id="P5">The TLR3 signaling pathway was investigated in the patient's fibroblasts by analyses of IFN-β, -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 EMSA and IRF-3 dimerization on native gels after stimulation with a TLR3 agonist.</p></sec><sec id="S4"><title>Results</title><p id="P6">The patient's fibroblasts displayed impaired responses to TLR3 stimulation in terms of IFN-β, -λ, and IL-6 production, owing to impaired activation of both NF-κB and IRF-3. Moreover, vesicular stomatitis virus (VSV), a potent IFN-inducer in human fibroblasts, and HSV-1, induced only low levels of IFN-β and -λ in the patient's fibroblasts, resulting in enhanced viral replication and cell death, as reported for UNC-93B-deficient fibroblasts.</p></sec><sec id="S5"><title>Conclusion</title><p id="P7">HSE may occur in patients carrying <italic>NEMO</italic> mutations, due to the impairment of NF-κB- and IRF-3-dependent-TLR3-mediated antiviral IFN production.</p></sec></abstract><kwd-group><kwd>NEMO</kwd><kwd>immunodeficiency</kwd><kwd>Toll-like receptor 3</kwd><kwd>herpes simplex encephalitis</kwd></kwd-group><funding-group><award-group><funding-source country="United States">National Center for Research Resources : NCRR</funding-source><award-id>UL1 RR024143-04 || RR</award-id></award-group><award-group><funding-source country="United States">National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID</funding-source><award-id>R01 AI088364-01 || AI</award-id></award-group></funding-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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