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Title: Virulence from vesicles: Novel mechanisms of host cell injury by Escherichia coli O104:H4 outbreak strain

item KUNSMANN, LISA - University Of Munster
item RUTER, CHRISTIAN - University Of Munster
item BAUWENS, ANDREAS - University Of Munster
item GREUNE, LILO - University Of Munster
item GLUDER, MALTE - University Of Munster
item KEMPER, BJORN - University Of Munster
item FRUTH, ANGELIKA - Robert Koch Institute
item WAI, SUN NYUNT - University Of Umea
item He, Xiaohua
item LLOUBES, ROLAND - Aix-Marseille University
item SCHMIDT, ALEXANDER - University Of Munster
item DOBRINDT, ULRICH - University Of Munster
item MELLMANN, ALEXANDER - University Of Munster
item KARCH, HELGE - University Of Munster
item BIELASZEWSKA, MARTINA - University Of Munster

Submitted to: Scientific Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/22/2015
Publication Date: 8/18/2015
Publication URL:
Citation: Kunsmann, L., Ruter, C., Bauwens, A., Greune, L., Gluder, M., Kemper, B., Fruth, A., Wai, S., He, X., Lloubes, R., Schmidt, A.M., Dobrindt, U., Mellmann, A., Karch, H., Bielaszewska, M. 2015. Virulence from vesicles: Novel mechanisms of host cell injury by Escherichia coli O104:H4 outbreak strain. Scientific Reports. doi: 10.1038/srep13252.

Interpretive Summary: Escherichia coli O104:H4, which caused a massive outbreak in 2011 with nearly 4000 infected persons, more than 900 cases of haemolytic uraemic syndrome (HUS) and 54 deaths, is a hybrid of enterohaemorrhagic (EHEC) and enteroaggregative (EAEC) E. coli. The strain harbors virulence genes from both of these E. coli. The mechanism of how the outbreak strain secretes its virulence factors is presently unknown. This research identified and characterized outer membrance vesicles (OMVs) from the E. coli O104:H4 outbreak strain and demonstrated that the bacterial strain released virulence factors via OMVs, which in turn are internalized by human intestinal cells and thereby delivered the virulence factors directly into the target cells, causing cell injury and inflammatory responses. This study also suggests that OMVs may be used as potential vaccine candidates to prevent disease caused by E. coli O104:H4.

Technical Abstract: The highly virulent Escherichia coli O104:H4 that caused the large 2011 outbreak of diarrhoea and haemolytic uraemic syndrome secretes blended virulence factors of enterohaemorrhagic and enteroaggregative E. coli, but their secretion pathways are unknown. We demonstrate that the outbreak strain releases a cocktail of virulence factors via outer membrane vesicles (OMVs) shed during growth. The OMVs contain Shiga toxin (Stx) 2a, the major virulence factor of the strain, Shigella enterotoxin 1, H4 flagellin, and O104 lipopolysaccharide. The OMVs bind to and are internalised by human intestinal epithelial cells via dynamin-dependent and Stx2a-independent endocytosis, deliver the OMV-associated virulence factors intracellularly and induce caspase-9-mediated apoptosis and interleukin-8 secretion. Stx2a is the key OMV component responsible for the cytotoxicity, whereas flagellin and lipopolysaccharide are the major interleukin-8 inducers. The OMVs represent novel ways for the E. coli O104:H4 outbreak strain to deliver pathogenic cargoes and injure host cells.