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In a patient experiencing multiple episodes of HSV-2 meningitis, we identified a monoallelic variant in the\n                    <jats:italic>IKBKE<\/jats:italic>\n                    gene, which encodes the IKK\u03b5 kinase involved in induction of antiviral IFN genes. Patient cells displayed impaired induction of IFN-\u03b21 (\n                    <jats:italic>IFNB1<\/jats:italic>\n                    ) expression upon infection with HSV-2 or stimulation with double-stranded DNA (dsDNA) and failed to induce phosphorylation of STING, an activation marker of the DNA-sensing cyclic GMP-AMP synthase\/stimulator of IFN genes (cGAS\/STING) pathway. The patient allele encoded a truncated IKK\u03b5 protein with loss of kinase activity and also capable of exerting dominant-negative activity. In stem cell\u2013derived microglia, HSV-2\u2013induced expression of\n                    <jats:italic>IFNB1<\/jats:italic>\n                    was dependent on\n                    <jats:italic>cGAS<\/jats:italic>\n                    , TANK binding kinase 1 (\n                    <jats:italic>TBK1<\/jats:italic>\n                    ), and\n                    <jats:italic>IKBKE<\/jats:italic>\n                    , but not\n                    <jats:italic>TLR3<\/jats:italic>\n                    , and supernatants from HSV-2\u2013treated microglia exerted\n                    <jats:italic>IKBKE<\/jats:italic>\n                    -dependent type I IFN\u2013mediated antiviral activity upon neurons. Reintroducing wild-type\n                    <jats:italic>IKBKE<\/jats:italic>\n                    into patient cells rescued\n                    <jats:italic>IFNB1<\/jats:italic>\n                    induction following treatment with HSV-2 or dsDNA and restored antiviral activity. Collectively, we identify IKK\u03b5 to be important for protection against HSV-2 meningitis and suggest a nonredundant role for the cGAS\/STING pathway in human antiviral immunity.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.173066","type":"journal-article","created":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T14:00:55Z","timestamp":1699365655000},"source":"Crossref","is-referenced-by-count":14,"title":["An IKBKE variant conferring functional cGAS\/STING pathway deficiency and susceptibility to recurrent HSV-2 meningitis"],"prefix":"10.1172","volume":"8","author":[{"given":"Azadeh","family":"Reyahi","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."},{"name":"Department of Biomedicine, Aarhus University, Aarhus, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Studahl","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Region V\u00e4stra G\u00f6taland, Sahlgrenska University Hospital, Gothenburg, Sweden."},{"name":"Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9358-5500","authenticated-orcid":true,"given":"Morten K.","family":"Skouboe","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, Aarhus, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Fruhw\u00fcrth","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Narita","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, Aarhus, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanghui","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, Aarhus, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moa","family":"Bjerhem Viklund","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie B.","family":"Iversen","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, Aarhus, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette","family":"Christiansen","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Svensson","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trine H.","family":"Mogensen","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, Aarhus, Denmark."},{"name":"Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Eriksson","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00f8ren R.","family":"Paludan","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden."},{"name":"Department of Biomedicine, Aarhus University, Aarhus, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2023,11,8]]},"reference":[{"key":"B1"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(00)04638-9"},{"key":"B3","first-page":"57","article-title":"La meningite endothelio-leucocytaire multirecurrente benigne. 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