title: A novel mechanism of bacterial toxin transfer within host blood cell-derived microvesicles.
abstract: Shiga toxin (Stx) is the main virulence factor of enterohemorrhagic Escherichia coli, which are non-invasive strains that can lead to hemolytic uremic syndrome (HUS), associated with renal failure and death. Although bacteremia does not occur, bacterial virulence factors gain access to the circulation and are thereafter presumed to cause target organ damage. Stx was previously shown to circulate bound to blood cells but the mechanism by which it would potentially transfer to target organ cells has not been elucidated. Here we show that blood cell-derived microvesicles, shed during HUS, contain Stx and are found within patient renal cortical cells. The finding was reproduced in mice infected with Stx-producing Escherichia coli exhibiting Stx-containing blood cell-derived microvesicles in the circulation that reached the kidney where they were transferred into glomerular and peritubular capillary endothelial cells and further through their basement membranes followed by podocytes and tubular epithelial cells, respectively. In vitro studies demonstrated that blood cell-derived microvesicles containing Stx undergo endocytosis in glomerular endothelial cells leading to cell death secondary to inhibited protein synthesis. This study demonstrates a novel virulence mechanism whereby bacterial toxin is transferred within host blood cell-derived microvesicles in which it may evade the host immune system.
authors.affiliation: Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Anne-lie
authors.initials: AL
authors.lastname: Ståhl
authors.affiliation: Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Ida
authors.initials: I
authors.lastname: Arvidsson
authors.affiliation: Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Karl E
authors.initials: KE
authors.lastname: Johansson
authors.affiliation: Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Milan
authors.initials: M
authors.lastname: Chromek
authors.affiliation: Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Rebetz
authors.affiliation: Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Loos
authors.affiliation: Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Kristoffersson
authors.affiliation: Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Zivile D
authors.initials: ZD
authors.lastname: Békássy
authors.affiliation: Division of Infection Medicine, Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.affiliation: Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Diana
authors.initials: D
authors.lastname: Karpman
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001427:Bacterial Toxins / Q000378:metabolism*; D001773:Blood Cells / Q000378:metabolism* / Q000382:microbiology; D055252:Cell-Derived Microparticles / Q000378:metabolism* / Q000382:microbiology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D054324:Enterohemorrhagic Escherichia coli / Q000378:metabolism*; D004927:Escherichia coli Infections / Q000378:metabolism* / Q000473:pathology; D005260:Female; D054884:Host-Pathogen Interactions; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D021381:Protein Transport
chemical_list: D001427:Bacterial Toxins