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

Autoři: Vincenzo Torraca aff001;  Myrsini Kaforou aff003;  Jayne Watson aff004;  Gina M. Duggan aff001;  Hazel Guerrero-Gutierrez aff001;  Sina Krokowski aff001;  Michael Hollinshead aff005;  Thomas B. Clarke aff001;  Rafal J. Mostowy aff006;  Gillian S. Tomlinson aff008;  Vanessa Sancho-Shimizu aff003;  Abigail Clements aff004;  Serge Mostowy aff001
Působiště autorů: Section of Microbiology, MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom aff001;  Department of Infection Biology, London School of Hygiene & Tropical Medicine, London, United Kingdom aff002;  Department of Paediatrics, Division of Medicine, Imperial College London, London, United Kingdom aff003;  Faculty of Natural Sciences, Department of Life Sciences, MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom aff004;  Division of Virology, Department of Pathology, Cambridge University, Cambridge, United Kingdom aff005;  Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland aff006;  Faculty of Medicine, School of Public Health, Imperial College London, London, United Kingdom aff007;  Division of Infection and Immunity, University College London, London, United Kingdom aff008;  Department of Virology, Division of Medicine, Imperial College London, London, United Kingdom aff009
Vyšlo v časopise: Shigella sonnei infection of zebrafish reveals that O-antigen mediates neutrophil tolerance and dysentery incidence. PLoS Pathog 15(12): e32767. doi:10.1371/journal.ppat.1008006
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008006


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.

Klíčová slova:

Larvae – Macrophages – Neutrophils – Shigella – Shigella flexneri – Shigellosis – Test statistics – Zebrafish


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