title: Protection against Shiga-Toxigenic Escherichia coli by Non-Genetically Modified Organism Receptor Mimic Bacterial Ghosts.
abstract: Shiga-toxigenic Escherichia coli (STEC) causes severe gastrointestinal infections in humans that may lead to life-threatening systemic sequelae, such as the hemolytic uremic syndrome (HUS). Rapid diagnosis of STEC infection early in the course of disease opens a window of opportunity for therapeutic intervention, for example, by administration of agents that neutralize Shiga toxin (Stx) in the gut lumen. We previously developed a recombinant bacterium that expresses a mimic of the Stx receptor globotriaosyl ceramide (Gb3) on its surface through modification of the lipopolysaccharide (A. W. Paton, R. Morona, and J. C. Paton, Nat Med 6:265-270, 2000, http://dx.doi.org/10.1038/73111). This construct was highly efficacious in vivo, protecting mice from otherwise fatal STEC disease, but the fact that it is a genetically modified organism (GMO) has been a barrier to clinical development. In the present study, we have overcome this issue by development of Gb3 receptor mimic bacterial ghosts (BGs) that are not classified as GMOs. Gb3-BGs neutralized Stx1 and Stx2 in vitro with high efficiency, whereas alternative Gb3-expressing non-GMO subbacterial particles (minicells and outer membrane blebs) were ineffective. Gb3-BGs were highly efficacious in a murine model of STEC disease. All mice (10/10) treated with Gb3-BGs survived challenge with a highly virulent O113:H21 STEC strain and showed no pathological signs of renal injury. In contrast, 6/10 mice treated with control BGs succumbed to STEC challenge, and survivors exhibited significant weight loss, neutrophilia, and histopathological evidence of renal damage. Thus, Gb3-BGs offer a non-GMO approach to treatment of STEC infection in humans, particularly in an outbreak setting.
authors.affiliation: Research Centre for Infectious Diseases, Department of Molecular and Cellular Biology, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Adrienne W
authors.initials: AW
authors.lastname: Paton
authors.affiliation: Research Centre for Infectious Diseases, Department of Molecular and Cellular Biology, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Austen Y
authors.initials: AY
authors.lastname: Chen
authors.affiliation: Research Centre for Infectious Diseases, Department of Molecular and Cellular Biology, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Research Centre for Infectious Diseases, Department of Molecular and Cellular Biology, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: McAllister
authors.affiliation: BIRD-C GmbH & Co. KG, Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Höggerl
authors.affiliation: BIRD-C GmbH & Co. KG, Vienna, Austria.
authors.forename: Ulrike Beate
authors.initials: UB
authors.lastname: Mayr
authors.affiliation: Institute for Glycomics, Griffith University, Gold Coast, Southport, Queensland, Australia.
authors.forename: Lucy K
authors.initials: LK
authors.lastname: Shewell
authors.affiliation: Institute for Glycomics, Griffith University, Gold Coast, Southport, Queensland, Australia.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Jennings
authors.affiliation: Research Centre for Infectious Diseases, Department of Molecular and Cellular Biology, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Renato
authors.initials: R
authors.lastname: Morona
authors.affiliation: BIRD-C GmbH & Co. KG, Vienna, Austria.
authors.forename: Werner
authors.initials: W
authors.lastname: Lubitz
authors.affiliation: Research Centre for Infectious Diseases, Department of Molecular and Cellular Biology, University of Adelaide, Adelaide, South Australia, Australia james.paton@adelaide.edu.au.
authors.forename: James C
authors.initials: JC
authors.lastname: Paton
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004927:Escherichia coli Infections / Q000517:prevention & control*; D005260:Female; D005915:Globosides / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018716:Molecular Mimicry; D030781:Organisms, Genetically Modified; D054323:Shiga-Toxigenic Escherichia coli; D014281:Trihexosylceramides / Q000276:immunology*
chemical_list: D005915:Globosides; D014281:Trihexosylceramides; C514780:globotrihexosylceramide