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https://hdl.handle.net/2440/100011
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Type: | Journal article |
Title: | Protection against Shiga-toxigenic Escherichia coli by non-genetically modified organism receptor mimic bacterial ghosts |
Author: | Paton, A. Chen, A. Wang, H. McAllister, L. Höggerl, F. Mayr, U. Shewell, L. Jennings, M. Morona, R. Lubitz, W. Paton, J. |
Citation: | Infection and Immunity, 2015; 83(9):3526-3533 |
Publisher: | American Society for Microbiology |
Issue Date: | 2015 |
ISSN: | 0019-9567 1098-5522 |
Editor: | Bäumler, A. |
Statement of Responsibility: | 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 |
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. |
Keywords: | Shiga-Toxigenic Escherichia coli |
Rights: | Copyright © 2015, American Society for Microbiology. All Rights Reserved. |
DOI: | 10.1128/IAI.00669-15 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/565526 http://purl.org/au-research/grants/nhmrc/1002792 http://purl.org/au-research/grants/arc/DP120103178 |
Published version: | http://dx.doi.org/10.1128/iai.00669-15 |
Appears in Collections: | Aurora harvest 7 Molecular and Biomedical Science publications |
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