ABSTRACTThe cytokine gamma interferon (IFN-γ) induces cell-autonomous immunity to combat infections with intracellular pathogens, such as the bacteriumChlamydia trachomatis. The present study demonstrates that IFN-γ-primed human cells ubiquitinate and eliminate intracellularChlamydia-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 pathogenChlamydia muridarumblocks 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 thatC. muridarumis susceptible to inclusion ubiquitination in human cells, while the closely related human pathogenC. trachomatisis resistant.C. muridarum, but notC. 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 ofC. muridarum, but notC. trachomatis, inclusions. This newly described defense pathway is independent of indole-2,3-dioxygenase, a known IFN-γ-inducible anti-Chlamydiaresistance factor. Collectively, our observations indicate thatC. trachomatisevolved mechanisms to avoid a human-specific, ubiquitin-mediated response as part of its unique adaptation to its human host.IMPORTANCEChlamydia trachomatisis 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. trachomatisis in perpetual conflict with cell-intrinsic defense programs executed by its human host. Our study defines a novel anti-Chlamydiahost resistance pathway active in human epithelial cells. This defense program promotes the deposition of the small antimicrobial protein ubiquitin on vacuoles containingChlamydia. We show that this ubiquitin-based resistance pathway of human cells is highly effective against aChlamydiaspecies adapted to rodents but ineffective against human-adaptedC. trachomatis. This observation indicates thatC. trachomatisevolved strategies to avoid entrapment within ubiquitin-labeled vacuoles as part of its adaptation to the human innate immune system.
Differential Effects of Gamma Interferon on Chlamydia trachomatis Growth in Polarized and Nonpolarized Human Epithelial Cells in Culture
