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2017-02-03Zeitschriftenartikel DOI: 10.1371/journal. ppat.1006159
Host cell interactions of outer membrane vesicle-associated virulence factors of enterohemorrhagic Escherichia coli O157: Intracellular delivery, trafficking and mechanisms of cell injury
dc.contributor.authorBielaszewska, Martina
dc.contributor.authorRüter, Christian
dc.contributor.authorBauwens, Andreas
dc.contributor.authorGreune, Lilo
dc.contributor.authorJarosch, Kevin-André
dc.contributor.authorSteil, Daniel
dc.contributor.authorZhang, Wenlan
dc.contributor.authorHe, Xiaohua
dc.contributor.authorLloubes, Roland
dc.contributor.authorFruth, Angelika
dc.contributor.authorKim, Kwang Sik
dc.contributor.authorSchmidt, M. Alexander
dc.contributor.authorDobrindt, Ulrich
dc.contributor.authorMellmann, Alexander
dc.contributor.authorKarch, Helge
dc.date.accessioned2018-05-07T19:46:23Z
dc.date.available2018-05-07T19:46:23Z
dc.date.created2017-02-23
dc.date.issued2017-02-03none
dc.identifier.otherhttp://edoc.rki.de/oa/articles/rezS7INXR3rH2/PDF/272xvVpPunDM.pdf
dc.identifier.urihttp://edoc.rki.de/176904/2559
dc.description.abstractOuter membrane vesicles (OMVs) are important tools in bacterial virulence but their role in the pathogenesis of infections caused by enterohemorrhagic Escherichia coli (EHEC) O157, the leading cause of life-threatening hemolytic uremic syndrome, is poorly understood. Using proteomics, electron and confocal laser scanning microscopy, immunoblotting, and bioassays, we investigated OMVs secreted by EHEC O157 clinical isolates for virulence factors cargoes, interactions with pathogenetically relevant human cells, and mechanisms of cell injury. We demonstrate that O157 OMVs carry a cocktail of key virulence factors of EHEC O157 including Shiga toxin 2a (Stx2a), cytolethal distending toxin V (CdtV), EHEC hemolysin, and flagellin. The toxins are internalized by cells via dynamin-dependent endocytosis of OMVs and differentially separate from vesicles during intracellular trafficking. Stx2a and CdtV-B, the DNase-like CdtV subunit, separate from OMVs in early endosomes. Stx2a is trafficked, in association with its receptor globotriaosylceramide within detergent-resistant membranes, to the Golgi complex and the endoplasmic reticulum from where the catalytic Stx2a A1 fragment is translocated to the cytosol. CdtV-B is, after its retrograde transport to the endoplasmic reticulum, translocated to the nucleus to reach DNA. CdtV-A and CdtV-C subunits remain OMV-associated and are sorted with OMVs to lysosomes. EHEC hemolysin separates from OMVs in lysosomes and targets mitochondria. The OMV-delivered CdtV-B causes cellular DNA damage, which activates DNA damage responses leading to G2 cell cycle arrest. The arrested cells ultimately die of apoptosis induced by Stx2a and CdtV via caspase-9 activation. By demonstrating that naturally secreted EHEC O157 OMVs carry and deliver into cells a cocktail of biologically active virulence factors, thereby causing cell death, and by performing first comprehensive analysis of intracellular trafficking of OMVs and OMV-delivered virulence factors, we provide new insights into the pathogenesis of EHEC O157 infections. Our data have implications for considering O157 OMVs as vaccine candidates.eng
dc.language.isoeng
dc.publisherRobert Koch-Institut, Infektionskrankheiten / Erreger
dc.subject.ddc610 Medizin
dc.titleHost cell interactions of outer membrane vesicle-associated virulence factors of enterohemorrhagic Escherichia coli O157: Intracellular delivery, trafficking and mechanisms of cell injury
dc.typeperiodicalPart
dc.identifier.urnurn:nbn:de:0257-10051315
dc.identifier.doi10.1371/journal. ppat.1006159
dc.identifier.doihttp://dx.doi.org/10.25646/2484
local.edoc.container-titlePLoS Pathogens
local.edoc.fp-subtypeArtikel
local.edoc.type-nameZeitschriftenartikel
local.edoc.container-typeperiodical
local.edoc.container-type-nameZeitschrift
local.edoc.container-urlhttp://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006159
local.edoc.container-publisher-namePublic Library of Science
local.edoc.container-volume13
local.edoc.container-issue2
local.edoc.container-year2017

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