title: Hemolysin of enterohemorrhagic Escherichia coli: structure, transport, biological activity and putative role in virulence.
abstract: Enterohemorrhagic Escherichia coli (EHEC) cause diarrhea, bloody diarrhea and hemolytic-uremic syndrome (HUS), a thrombotic microangiopathy affecting the renal glomeruli, the intestine, and the brain. The pathogenesis of EHEC-mediated diseases is incompletely understood. In addition to Shiga toxins, the major virulence factors of EHEC, the contribution of EHEC hemolysin (EHEC-Hly), also designated EHEC toxin (Ehx), which is a member of the RTX (repeats-in-toxin) family, is increasingly recognized. The toxin and its activation and secretion machinery are encoded by the EHEC-hlyCABD operon, in which EHEC-hlyA is the structural gene for EHEC-Hly and the EHEC-hlyC product mediates post-translational activation of EHEC-Hly; the EHEC-hlyB- and EHEC-hlyD-encoded proteins form, together with genetically unlinked TolC, the type I secretion system that transports EHEC-Hly out of the bacterial cell. EHEC-Hly exists in two biologically active forms: as a free EHEC-Hly, and an EHEC-Hly associated with outer membrane vesicles (OMVs) that are released by EHEC during growth. The OMV-associated form results from a rapid binding of free EHEC-Hly to OMVs upon its extracellular secretion. The OMV association stabilizes EHEC-Hly and thus substantially prolongs its hemolytic activity compared to the free toxin. The two EHEC-Hly forms differ by their mechanism of toxicity toward human intestinal epithelial and microvascular endothelial cells, which are the major targets during EHEC infection. The free EHEC-Hly lyses human microvascular endothelial cells, presumably by pore formation in the cell membrane. In contrast, the OMV-associated EHEC-Hly does not lyse any of these cell types, but after its cellular internalization via OMVs it targets mitochondria and triggers caspase-9-mediated apoptosis. The proinflammatory potential of EHEC-Hly, in particular its ability to elicit secretion of interleukin-1β from human monocytes/macrophages, might be an additional mechanism of its putative contribution to the pathogenesis of EHEC-mediated diseases. Increasing understanding of molecular mechanisms underlying interaction of EHEC-Hly with target cells as well as the host cell responses to the toxin supports the involvement of EHEC-Hly in the pathogenesis of EHEC-mediated diseases and forms a basis for prevention of the EHEC-Hly-mediated injury during human infection.
authors.affiliation: Institute of Hygiene, University of Münster, Robert-Koch-Str. 41, 48149 Münster, Germany. Electronic address: mbiela@uni-muenster.de.
authors.forename: Martina
authors.initials: M
authors.lastname: Bielaszewska
authors.affiliation: Institute of Hygiene, University of Münster, Robert-Koch-Str. 41, 48149 Münster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Aldick
authors.affiliation: Institute of Hygiene, University of Münster, Robert-Koch-Str. 41, 48149 Münster, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bauwens
authors.affiliation: Institute of Hygiene, University of Münster, Robert-Koch-Str. 41, 48149 Münster, Germany.
authors.forename: Helge
authors.initials: H
authors.lastname: Karch
mesh_terms: D017209:Apoptosis; D001692:Biological Transport; D042783:Endothelial Cells / Q000187:drug effects; D054324:Enterohemorrhagic Escherichia coli / Q000235:genetics / Q000254:growth & development* / Q000472:pathogenicity; D004847:Epithelial Cells / Q000187:drug effects; D006460:Hemolysin Proteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D006801:Humans; D009876:Operon; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*
chemical_list: D006460:Hemolysin Proteins; D037521:Virulence Factors
keywords: Apoptosis; Cell lysis; EHEC hemolysin (EHEC-Hly); EHEC toxin (Ehx); Enterohemolysin; Enterohemolytic phenotype; Mitochondria; Outer membrane vesicles; RTX toxin