title: Chlamydia trachomatis Is Resistant to Inclusion Ubiquitination and Associated Host Defense in Gamma Interferon-Primed Human Epithelial Cells.
abstract: The cytokine gamma interferon (IFN-γ) induces cell-autonomous immunity to combat infections with intracellular pathogens, such as the bacterium Chlamydia trachomatis The present study demonstrates that IFN-γ-primed human cells ubiquitinate and eliminate intracellular Chlamydia-containing vacuoles, so-called inclusions. We previously described how IFN-γ-inducible immunity-related GTPases (IRGs) employ ubiquitin systems to mark inclusions for destruction in mouse cells and, furthermore, showed that the rodent pathogen Chlamydia muridarum 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 C. muridarum is susceptible to inclusion ubiquitination in human cells, while the closely related human pathogen C. trachomatis is resistant. C. muridarum, but not C. trachomatis, 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-γ priming of human epithelial cells triggers the elimination of C. muridarum, but not C. trachomatis, inclusions. This newly described defense pathway is independent of indole-2,3-dioxygenase, a known IFN-γ-inducible anti-Chlamydia resistance factor. Collectively, our observations indicate that C. trachomatis evolved mechanisms to avoid a human-specific, ubiquitin-mediated response as part of its unique adaptation to its human host.
  
  
  
  Chlamydia trachomatis 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, C. trachomatis is in perpetual conflict with cell-intrinsic defense programs executed by its human host. Our study defines a novel anti-Chlamydia host resistance pathway active in human epithelial cells. This defense program promotes the deposition of the small antimicrobial protein ubiquitin on vacuoles containing Chlamydia We show that this ubiquitin-based resistance pathway of human cells is highly effective against a Chlamydia species adapted to rodents but ineffective against human-adapted C. trachomatis This observation indicates that C. trachomatis evolved strategies to avoid entrapment within ubiquitin-labeled vacuoles as part of its adaptation to the human innate immune system.
authors.affiliation: Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Haldar
authors.affiliation: Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Piro
authors.affiliation: Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Finethy
authors.affiliation: Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Espenschied
authors.affiliation: Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Hannah E
authors.initials: HE
authors.lastname: Brown
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Giebel
authors.affiliation: The Francis Crick Institute, Host-Toxoplasma Interaction Laboratory, London, United Kingdom.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Frickel
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Nelson
authors.affiliation: Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, North Carolina, USA jorn.coers@duke.edu.
authors.forename: Jörn
authors.initials: J
authors.lastname: Coers
mesh_terms: D000072283:A549 Cells; D000818:Animals; D023502:Chlamydia muridarum / Q000276:immunology / Q000502:physiology; D002692:Chlamydia trachomatis / Q000276:immunology* / Q000502:physiology*; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D019204:GTP-Binding Proteins / Q000378:metabolism; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D002479:Inclusion Bodies / Q000187:drug effects / Q000382:microbiology; D007371:Interferon-gamma / Q000276:immunology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D054875:Ubiquitination; D014617:Vacuoles / Q000382:microbiology
chemical_list: C490287:GBP1 protein, human; C573415:IFNG protein, human; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D007371:Interferon-gamma; D019204:GTP-Binding Proteins