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Cell Death Differ. 2018 Oct 30. doi: 10.1038/s41418-018-0224-2. [Epub ahead of print]

Chlamydia trachomatis fails to protect its growth niche against pro-apoptotic insults.

Sixt BS1,2,3,4,5, Núñez-Otero C6, Kepp O7,8,9,10, Valdivia RH11, Kroemer G12,13,14,15,16,17.

Author information

1
Laboratory for Molecular Infection Medicine Sweden, Umeå Centre for Microbial Research, Department of Molecular Biology, Umeå University, 90187, Umeå, Sweden. barbara.sixt@umu.se.
2
INSERM U1138, Centre de Recherche des Cordeliers, 75006, Paris, France. barbara.sixt@umu.se.
3
Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, 75006, Paris, France. barbara.sixt@umu.se.
4
Université Paris Descartes, 75006, Paris, France. barbara.sixt@umu.se.
5
Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94800, Villejuif, France. barbara.sixt@umu.se.
6
Laboratory for Molecular Infection Medicine Sweden, Umeå Centre for Microbial Research, Department of Clinical Microbiology, Umeå University, 90185, Umeå, Sweden.
7
INSERM U1138, Centre de Recherche des Cordeliers, 75006, Paris, France.
8
Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, 75006, Paris, France.
9
Université Paris Descartes, 75006, Paris, France.
10
Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94800, Villejuif, France.
11
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, 27710, USA.
12
INSERM U1138, Centre de Recherche des Cordeliers, 75006, Paris, France. kroemer@orange.fr.
13
Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, 75006, Paris, France. kroemer@orange.fr.
14
Université Paris Descartes, 75006, Paris, France. kroemer@orange.fr.
15
Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94800, Villejuif, France. kroemer@orange.fr.
16
Pôle de Biologie, Hôpital Européen Georges-Pompidou, AP-HP, 75015, Paris, France. kroemer@orange.fr.
17
Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, 17176, Stockholm, Sweden. kroemer@orange.fr.

Abstract

Chlamydia trachomatis is an obligate intracellular bacterial agent responsible for ocular infections and sexually transmitted diseases. It has been postulated that Chlamydia inhibits apoptosis in host cells to maintain an intact replicative niche until sufficient infectious progeny can be generated. Here we report that, while cells infected with C. trachomatis are protected from apoptosis at early and mid-stages of infection, they remain susceptible to the induction of other cell death modalities. By monitoring the fate of infected cells by time-lapse video microscopy and by analyzing host plasma membrane integrity and the activity of caspases, we determined that C. trachomatis-infected cells exposed to pro-apoptotic stimuli predominately died by a mechanism resembling necrosis. This necrotic death of infected cells occurred with kinetics similar to the induction of apoptosis in uninfected cells, indicating that C. trachomatis fails to considerably prolong the lifespan of its host cell when exposed to pro-apoptotic insults. Inhibitors of bacterial protein synthesis partially blocked necrotic death of infected cells, suggesting that the switch from apoptosis to necrosis relies on an active contribution of the bacteria. Tumor necrosis factor alpha (TNF-α)-mediated induction of necrosis in cells infected with C. trachomatis was not dependent on canonical regulators of necroptosis, such as RIPK1, RIPK3, or MLKL, yet was blocked by inhibition or depletion of CASP8. These results suggest that alternative signaling pathways regulate necrotic death in the context of C. trachomatis infections. Finally, consistent with the inability of C. trachomatis to preserve host cell viability, necrosis resulting from pro-apoptotic conditions significantly impaired production of infectious progeny. Taken together, our findings suggest that Chlamydia's anti-apoptotic activities are not sufficient to protect the pathogen's replicative niche.

PMID:
30375511
DOI:
10.1038/s41418-018-0224-2

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