Affiliation:
1. Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, North Carolina, USA
2. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA
3. The Francis Crick Institute, Host-Toxoplasma Interaction Laboratory, London, United Kingdom
Abstract
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.
IMPORTANCE
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.
Publisher
American Society for Microbiology
Cited by
40 articles.
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