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dc.contributor.authorTorraca, Vincenzo
dc.contributor.authorKaforou, Myrsini
dc.contributor.authorWatson, Jayne
dc.contributor.authorDuggan, Gina M.
dc.contributor.authorGuerrero-Gutierrez, Hazel
dc.contributor.authorKrokowski, Sina
dc.contributor.authorHollinshead, Michael
dc.contributor.authorClarke, Thomas B.
dc.contributor.authorMostowy, Rafal J.
dc.contributor.authorTomlinson, Gillian S.
dc.contributor.authorSancho-Shimizu, Vanessa
dc.contributor.authorClements, Abigail
dc.contributor.authorMostowy, Serge
dc.date.accessioned2020-01-25T00:12:24Z
dc.date.available2020-01-25T00:12:24Z
dc.date.issued2019-12-12
dc.date.submitted2019-07-24
dc.identifier.issn1553-7366
dc.identifier.otherppathogens-d-19-01349
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/301238
dc.descriptionFunder: Lister Institute of Preventive Medicine; funder-id: http://dx.doi.org/10.13039/501100001255
dc.description.abstractShigella 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.
dc.languageen
dc.rightsAttribution 4.0 International (CC BY 4.0)en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectResearch Article
dc.subjectBiology and life sciences
dc.subjectMedicine and health sciences
dc.subjectResearch and analysis methods
dc.subjectPhysical sciences
dc.titleShigella sonnei infection of zebrafish reveals that O-antigen mediates neutrophil tolerance and dysentery incidence
dc.typeArticle
dc.date.updated2020-01-25T00:12:24Z
dc.identifier.doi10.17863/CAM.48321
dcterms.dateAccepted2019-11-01
rioxxterms.versionofrecord10.1371/journal.ppat.1008006
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
datacite.contributor.supervisoreditor: Mulvey, Matthew A.
dc.contributor.orcidTorraca, Vincenzo [0000-0001-7340-0249]
dc.contributor.orcidKaforou, Myrsini [0000-0001-9878-4007]
dc.contributor.orcidWatson, Jayne [0000-0002-4451-4113]
dc.contributor.orcidGuerrero-Gutierrez, Hazel [0000-0003-1701-0208]
dc.contributor.orcidMostowy, Rafal J. [0000-0002-4557-3748]
dc.contributor.orcidSancho-Shimizu, Vanessa [0000-0002-3519-0727]
dc.contributor.orcidClements, Abigail [0000-0003-2285-777X]
dc.contributor.orcidMostowy, Serge [0000-0002-7286-6503]
dc.identifier.eissn1553-7374
pubs.funder-project-idHorizon 2020 Framework Programme (H2020-MSCA-IF-2015 – 700088)
pubs.funder-project-idEuropean Research Council (772853 - ENTRAPMENT)
pubs.funder-project-idWellcome Trust (206444/Z/17/Z))
pubs.funder-project-idWellcome Trust (WT097411MA)


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Attribution 4.0 International (CC BY 4.0)
Except where otherwise noted, this item's licence is described as Attribution 4.0 International (CC BY 4.0)