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Nat Microbiol. 2020 Feb;5(2):354-367. doi: 10.1038/s41564-019-0620-5. Epub 2019 Dec 23.

Cytosolic Gram-negative bacteria prevent apoptosis by inhibition of effector caspases through lipopolysaccharide.

Author information

1
Institute for Medical Microbiology, Immunology and Hygiene, Centre for Molecular Medicine Cologne and Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases, University of Cologne, Cologne, Germany.
2
Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany.
3
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
4
Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.
5
Institute for Medical Microbiology, Immunology and Hygiene, Centre for Molecular Medicine Cologne and German Centre for Infection Research, Partner Site Bonn-Cologne, University of Cologne, Cologne, Germany.
6
Gene Centre and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.
7
Department of Biology and Biotechnology "Charles Darwin", Sapienza-Università di Roma, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy.
8
Institute for Biochemistry I, University of Cologne, Cologne, Germany.
9
Institute for Medical Microbiology, Immunology and Hygiene, Centre for Molecular Medicine Cologne and Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases, University of Cologne, Cologne, Germany. h.kashkar@uni-koeln.de.

Abstract

The cytosolic appearance and propagation of bacteria cause overwhelming cellular stress responses that induce apoptosis under normal conditions. Therefore, successful bacterial colonization depends on the ability of intracellular pathogens to block apoptosis and to safeguard bacterial replicative niches. Here, we show that the cytosolic Gram-negative bacterium Shigella flexneri stalls apoptosis by inhibiting effector caspase activity. Our data identified lipopolysaccharide (LPS) as a bona fide effector caspase inhibitor that directly binds caspases by involving its O-antigen (O Ag) moiety. Bacterial strains that lacked the O Ag or failed to replicate within the cytosol were incapable of blocking apoptosis and exhibited reduced virulence in a murine model of bacterial infection. Our findings demonstrate how Shigella inhibits pro-apoptotic caspase activity, effectively delays coordinated host-cell demise and supports its intracellular propagation. Next to the recently discovered pro-inflammatory role of cytosolic LPS, our data reveal a distinct mode of LPS action that, through the disruption of the early coordinated non-lytic cell death response, ultimately supports the inflammatory breakdown of infected cells at later time points.

PMID:
31873204
DOI:
10.1038/s41564-019-0620-5

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