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: Adrienne W Paton, Austen Y Chen, Hui Wang, Lauren J McAllister, Florian Höggerl, Ulrike Beate Mayr, Lucy K Shewell, Michael P Jennings, Renato Morona, Werner Lubitz, James C Paton
• Journal: Infection and immunity (Infect Immun) Vol. 83 Issue 9 Pg. 3526-33 (Sep 2015) ISSN: 1098-5522 [Electronic] United States
• PMID: 26099582 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• Globosides
• Trihexosylceramides
• globotrihexosylceramide

Topics

• Animals
• Disease Models, Animal
• Escherichia coli Infections (prevention & control)
• Female
• Globosides (immunology)
• Mice
• Mice, Inbred BALB C
• Molecular Mimicry
• Organisms, Genetically Modified
• Shiga-Toxigenic Escherichia coli
• Trihexosylceramides (immunology)