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Chlamydia trachomatis Is Resistant to Inclusion Ubiquitination and Associated Host Defense in Gamma Interferon-Primed Human Epithelial Cells.

Publication ,  Journal Article
Haldar, AK; Piro, AS; Finethy, R; Espenschied, ST; Brown, HE; Giebel, AM; Frickel, E-M; Nelson, DE; Coers, J
Published in: mBio
December 13, 2016

UNLABELLED: 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.

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Published In

mBio

DOI

EISSN

2150-7511

Publication Date

December 13, 2016

Volume

7

Issue

6

Location

United States

Related Subject Headings

  • Vacuoles
  • Ubiquitination
  • Microtubule-Associated Proteins
  • Mice
  • Interferon-gamma
  • Inclusion Bodies
  • Immunity, Innate
  • Humans
  • Host-Pathogen Interactions
  • Hela Cells
 

Citation

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Haldar, 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). https://doi.org/10.1128/mBio.01417-16
Haldar, Arun K., Anthony S. Piro, Ryan Finethy, Scott T. Espenschied, Hannah E. Brown, Amanda M. Giebel, Eva-Maria Frickel, David E. Nelson, and Jörn Coers. “Chlamydia trachomatis Is Resistant to Inclusion Ubiquitination and Associated Host Defense in Gamma Interferon-Primed Human Epithelial Cells.MBio 7, no. 6 (December 13, 2016). https://doi.org/10.1128/mBio.01417-16.
Haldar AK, Piro AS, Finethy R, Espenschied ST, Brown HE, Giebel AM, et al. Chlamydia trachomatis Is Resistant to Inclusion Ubiquitination and Associated Host Defense in Gamma Interferon-Primed Human Epithelial Cells. mBio. 2016 Dec 13;7(6).
Haldar, Arun K., et al. “Chlamydia trachomatis Is Resistant to Inclusion Ubiquitination and Associated Host Defense in Gamma Interferon-Primed Human Epithelial Cells.MBio, vol. 7, no. 6, Dec. 2016. Pubmed, doi:10.1128/mBio.01417-16.
Haldar AK, Piro AS, Finethy R, Espenschied ST, Brown HE, Giebel AM, Frickel E-M, Nelson DE, Coers J. Chlamydia trachomatis Is Resistant to Inclusion Ubiquitination and Associated Host Defense in Gamma Interferon-Primed Human Epithelial Cells. mBio. 2016 Dec 13;7(6).

Published In

mBio

DOI

EISSN

2150-7511

Publication Date

December 13, 2016

Volume

7

Issue

6

Location

United States

Related Subject Headings

  • Vacuoles
  • Ubiquitination
  • Microtubule-Associated Proteins
  • Mice
  • Interferon-gamma
  • Inclusion Bodies
  • Immunity, Innate
  • Humans
  • Host-Pathogen Interactions
  • Hela Cells