Haldar, Arun K.Piro, Anthony S.Finethy, RyanEspenschied, Scott T.Brown, Hannah E.Giebel, Amanda M.Frickel, Eva-MariaNelson, David E.Coers, Jörn2017-06-142017-06-142016-12-13Haldar, A. K., Piro, A. S., Finethy, R., Espenschied, S. T., Brown, H. E., Giebel, A. M., … Coers, J. (2016). Chlamydia trachomatis Is Resistant to Inclusion Ubiquitination and Associated Host Defense in Gamma Interferon-Primed Human Epithelial Cells. mBio, 7(6), e01417–16. http://doi.org/10.1128/mBio.01417-16https://hdl.handle.net/1805/13045The 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.en-USAttribution-NonCommercial-NoDerivs 3.0 United StatesCytokine gamma interferon (IFN-γ)Chlamydia trachomatisCellsCell-autonomous immunityImmunity-related GTPases (IRGs)Chlamydia muridarumArticle