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PLoS Pathog. 2019 Dec 12;15(12):e1008006. doi: 10.1371/journal.ppat.1008006. eCollection 2019 Dec.

Shigella sonnei infection of zebrafish reveals that O-antigen mediates neutrophil tolerance and dysentery incidence.

Author information

1
Section of Microbiology, MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom.
2
Department of Infection Biology, London School of Hygiene & Tropical Medicine, London, United Kingdom.
3
Department of Paediatrics, Division of Medicine, Imperial College London, London, United Kingdom.
4
Faculty of Natural Sciences, Department of Life Sciences, MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom.
5
Division of Virology, Department of Pathology, Cambridge University, Cambridge, United Kingdom.
6
Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland.
7
Faculty of Medicine, School of Public Health, Imperial College London, London, United Kingdom.
8
Division of Infection and Immunity, University College London, London, United Kingdom.
9
Department of Virology, Division of Medicine, Imperial College London, London, United Kingdom.

Abstract

Shigella flexneri is historically regarded as the primary agent of bacillary dysentery, yet the closely-related Shigella sonnei is replacing S. flexneri, especially in developing countries. The underlying reasons for this dramatic shift are mostly unknown. Using a zebrafish (Danio rerio) model of Shigella infection, we discover that S. sonnei is more virulent than S. flexneri in vivo. Whole animal dual-RNAseq and testing of bacterial mutants suggest that S. sonnei virulence depends on its O-antigen oligosaccharide (which is unique among Shigella species). We show in vivo using zebrafish and ex vivo using human neutrophils that S. sonnei O-antigen can mediate neutrophil tolerance. Consistent with this, we demonstrate that O-antigen enables S. sonnei to resist phagolysosome acidification and promotes neutrophil cell death. Chemical inhibition or promotion of phagolysosome maturation respectively decreases and increases neutrophil control of S. sonnei and zebrafish survival. Strikingly, larvae primed with a sublethal dose of S. sonnei are protected against a secondary lethal dose of S. sonnei in an O-antigen-dependent manner, indicating that exposure to O-antigen can train the innate immune system against S. sonnei. Collectively, these findings reveal O-antigen as an important therapeutic target against bacillary dysentery, and may explain the rapidly increasing S. sonnei burden in developing countries.

PMID:
31830135
DOI:
10.1371/journal.ppat.1008006
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Conflict of interest statement

The authors have declared that no competing interests exist.

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