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

Vincenzo Torraca, Myrsini Kaforou, Jayne Watson, Gina M. Duggan, Hazel Guerrero-Gutierrez, Sina Krokowski, Michael Hollinshead, Thomas B. Clarke, Rafal J. Mostowy, Gillian S. Tomlinson, Vanessa Sancho-Shimizu, Abigail Clements and Serge Mostowy 2019. Shigella sonnei infection of zebrafish reveals that O-antigen mediates neutrophil tolerance and dysentery incidence. PLOS Pathogens. 15 (12) e1008006. https://doi.org/10.1371/journal.ppat.1008006

TitleShigella sonnei infection of zebrafish reveals that O-antigen mediates neutrophil tolerance and dysentery incidence
TypeJournal article
AuthorsVincenzo Torraca, Myrsini Kaforou, Jayne Watson, Gina M. Duggan, Hazel Guerrero-Gutierrez, Sina Krokowski, Michael Hollinshead, Thomas B. Clarke, Rafal J. Mostowy, Gillian S. Tomlinson, Vanessa Sancho-Shimizu, Abigail Clements and Serge Mostowy
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.

Article numbere1008006
JournalPLOS Pathogens
Journal citation15 (12)
ISSN1553-7374
Year2019
PublisherPublic Library of Science
Publisher's version
License
CC BY 4.0
File Access Level
Open (open metadata and files)
Digital Object Identifier (DOI)https://doi.org/10.1371/journal.ppat.1008006
Publication dates
Published12 Dec 2019
EditorsMatthew A. Mulvey

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