{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T12:15:21Z","timestamp":1790511321717,"version":"4.1.0"},"reference-count":55,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2016,12,13]],"date-time":"2016-12-13T00:00:00Z","timestamp":1481587200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2016,12,30]],"date-time":"2016-12-30T00:00:00Z","timestamp":1483056000000},"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":[[2016,12,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>The cytokine gamma interferon (IFN-\u03b3) induces cell-autonomous immunity to combat infections with intracellular pathogens, such as the bacterium<jats:named-content content-type=\"genus-species\">Chlamydia trachomatis<\/jats:named-content>. The present study demonstrates that IFN-\u03b3-primed human cells ubiquitinate and eliminate intracellular<jats:italic>Chlamydia<\/jats:italic>-containing vacuoles, so-called inclusions. We previously described how IFN-\u03b3-inducible immunity-related GTPases (IRGs) employ ubiquitin systems to mark inclusions for destruction in mouse cells and, furthermore, showed that the rodent pathogen<jats:named-content content-type=\"genus-species\">Chlamydia muridarum<\/jats:named-content>blocks ubiquitination of its inclusions by interfering with mouse IRG function. Here, we report that ubiquitination of inclusions in human cells is independent of IRG and thus distinct from the murine pathway. We show that<jats:named-content content-type=\"genus-species\">C. muridarum<\/jats:named-content>is susceptible to inclusion ubiquitination in human cells, while the closely related human pathogen<jats:named-content content-type=\"genus-species\">C. trachomatis<\/jats:named-content>is resistant.<jats:named-content content-type=\"genus-species\">C. muridarum<\/jats:named-content>, but not<jats:named-content content-type=\"genus-species\">C. trachomatis<\/jats:named-content>, inclusions attract several markers of cell-autonomous immunity, including the ubiquitin-binding protein p62, the ubiquitin-like protein LC3, and guanylate-binding protein 1. Consequently, we find that IFN-\u03b3 priming of human epithelial cells triggers the elimination of<jats:named-content content-type=\"genus-species\">C. muridarum<\/jats:named-content>, but not<jats:named-content content-type=\"genus-species\">C. trachomatis<\/jats:named-content>, inclusions. This newly described defense pathway is independent of indole-2,3-dioxygenase, a known IFN-\u03b3-inducible anti-<jats:italic>Chlamydia<\/jats:italic>resistance factor. Collectively, our observations indicate that<jats:named-content content-type=\"genus-species\">C. trachomatis<\/jats:named-content>evolved mechanisms to avoid a human-specific, ubiquitin-mediated response as part of its unique adaptation to its human host.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold><jats:named-content content-type=\"genus-species\">Chlamydia trachomatis<\/jats:named-content>is the leading cause of sexually transmitted bacterial infections and responsible for significant morbidity, including pelvic inflammatory disease, infertility, and ectopic pregnancies in women. As an obligate intracellular pathogen,<jats:named-content content-type=\"genus-species\">C. trachomatis<\/jats:named-content>is in perpetual conflict with cell-intrinsic defense programs executed by its human host. Our study defines a novel anti-<jats:italic>Chlamydia<\/jats:italic>host resistance pathway active in human epithelial cells. This defense program promotes the deposition of the small antimicrobial protein ubiquitin on vacuoles containing<jats:italic>Chlamydia<\/jats:italic>. We show that this ubiquitin-based resistance pathway of human cells is highly effective against a<jats:italic>Chlamydia<\/jats:italic>species adapted to rodents but ineffective against human-adapted<jats:named-content content-type=\"genus-species\">C. trachomatis<\/jats:named-content>. This observation indicates that<jats:named-content content-type=\"genus-species\">C. trachomatis<\/jats:named-content>evolved strategies to avoid entrapment within ubiquitin-labeled vacuoles as part of its adaptation to the human innate immune system.<\/jats:p>","DOI":"10.1128\/mbio.01417-16","type":"journal-article","created":{"date-parts":[[2016,12,14]],"date-time":"2016-12-14T01:25:26Z","timestamp":1481678726000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":59,"title":["Chlamydia trachomatis Is Resistant to Inclusion Ubiquitination and Associated Host Defense in Gamma Interferon-Primed Human Epithelial Cells"],"prefix":"10.1128","volume":"7","author":[{"given":"Arun K.","family":"Haldar","sequence":"first","affiliation":[{"name":"Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony S.","family":"Piro","sequence":"additional","affiliation":[{"name":"Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Finethy","sequence":"additional","affiliation":[{"name":"Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott T.","family":"Espenschied","sequence":"additional","affiliation":[{"name":"Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah E.","family":"Brown","sequence":"additional","affiliation":[{"name":"Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda M.","family":"Giebel","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva-Maria","family":"Frickel","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute, Host-Toxoplasma Interaction Laboratory, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David E.","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rn","family":"Coers","sequence":"additional","affiliation":[{"name":"Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","volume-title":"Global prevalence and incidence of selected curable sexually transmitted diseases: overview and estimates","author":"World Health Organization","year":"2011","unstructured":"World Health Organization. 2011. 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