{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T00:50:14Z","timestamp":1793839814468,"version":"4.6.1"},"reference-count":74,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2013,4,30]],"date-time":"2013-04-30T00:00:00Z","timestamp":1367280000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2013,7,1]],"date-time":"2013-07-01T00:00:00Z","timestamp":1372636800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2013,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    STING (\n                    <jats:underline>s<\/jats:underline>\n                    <jats:underline>t<\/jats:underline>\n                    <jats:underline>i<\/jats:underline>\n                    mulator of interfero\n                    <jats:underline>n<\/jats:underline>\n                    [IFN]\n                    <jats:underline>g<\/jats:underline>\n                    enes) initiates type I IFN responses in mammalian cells through the detection of microbial nucleic acids. The membrane-bound obligate intracellular bacterium\n                    <jats:named-content content-type=\"genus-species\">Chlamydia trachomatis<\/jats:named-content>\n                    induces a STING-dependent type I IFN response in infected cells, yet the IFN-inducing ligand remains unknown. In this report, we provide evidence that\n                    <jats:italic>Chlamydia<\/jats:italic>\n                    synthesizes cyclic di-AMP (c-di-AMP), a nucleic acid metabolite not previously identified in Gram-negative bacteria, and that this metabolite is a prominent ligand for STING-mediated activation of IFN responses during infection. We used primary mouse lung fibroblasts and HEK293T cells to compare IFN-\u03b2 responses to\n                    <jats:italic>Chlamydia<\/jats:italic>\n                    infection, c-di-AMP, and other type I IFN-inducing stimuli.\n                    <jats:italic>Chlamydia<\/jats:italic>\n                    infection and c-di-AMP treatment induced type I IFN responses in cells expressing STING but not in cells expressing STING variants that cannot sense cyclic dinucleotides but still respond to cytoplasmic DNA. The failure to induce a type I IFN response to\n                    <jats:italic>Chlamydia<\/jats:italic>\n                    and c-di-AMP correlated with the inability of STING to relocalize from the endoplasmic reticulum to cytoplasmic punctate signaling complexes required for IFN activation. We conclude that\n                    <jats:italic>Chlamydia<\/jats:italic>\n                    induces STING-mediated IFN responses through the detection of c-di-AMP in the host cell cytosol and propose that c-di-AMP is the ligand predominantly responsible for inducing such a response in\n                    <jats:italic>Chlamydia<\/jats:italic>\n                    -infected cells.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    This study shows that the Gram-negative obligate pathogen\n                    <jats:named-content content-type=\"genus-species\">Chlamydia trachomatis<\/jats:named-content>\n                    , a major cause of pelvic inflammatory disease and infertility, synthesizes cyclic di-AMP (c-di-AMP), a nucleic acid metabolite that thus far has been described only in Gram-positive bacteria. We further provide evidence that the host cell employs an endoplasmic reticulum (ER)-localized cytoplasmic sensor, STING (\n                    <jats:underline>s<\/jats:underline>\n                    <jats:underline>t<\/jats:underline>\n                    <jats:underline>i<\/jats:underline>\n                    mulator of interfero\n                    <jats:underline>n<\/jats:underline>\n                    [IFN]\n                    <jats:underline>g<\/jats:underline>\n                    enes), to detect c-di-AMP synthesized by\n                    <jats:italic>Chlamydia<\/jats:italic>\n                    and induce a protective IFN response. This detection occurs even though\n                    <jats:italic>Chlamydia<\/jats:italic>\n                    is confined to a membrane-bound vacuole. This raises the possibility that the ER, an organelle that innervates the entire cytoplasm, is equipped with pattern recognition receptors that can directly survey membrane-bound pathogen-containing vacuoles for leaking microbe-specific metabolites to mount type I IFN responses required to control microbial infections.\n                  <\/jats:p>","DOI":"10.1128\/mbio.00018-13","type":"journal-article","created":{"date-parts":[[2013,5,1]],"date-time":"2013-05-01T09:08:28Z","timestamp":1367399308000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":234,"title":["STING-Dependent Recognition of Cyclic di-AMP Mediates Type I Interferon Responses during Chlamydia trachomatis Infection"],"prefix":"10.1128","volume":"4","author":[{"given":"Jeffrey R.","family":"Barker","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Center for Microbial Pathogenesis, Duke University, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin J.","family":"Koestler","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria K.","family":"Carpenter","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Center for Microbial Pathogenesis, Duke University, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dara L.","family":"Burdette","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Waters","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell E.","family":"Vance","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael H.","family":"Valdivia","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Center for Microbial Pathogenesis, Duke University, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1086\/652395"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.femsre.2005.03.002"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0703218104"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.01.022"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2010.01478.x"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvm032"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2397"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00629-08"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20040976"},{"key":"e_1_3_2_11_2","doi-asserted-by":"crossref","unstructured":"GratzN\nHartwegerH\nMattU\nKratochvillF\nJanosM\nSigelS\nDrobitsB\nLiXD\nKnappS\nKovarikP\n. 2011. 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