Exploiting effector networks for attenuated vaccine design in A/E pathogenesis
File(s)
Author(s)
Jordan, Sarah
Type
Thesis or dissertation
Abstract
Enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic E. coli (EHEC) are extracellular enteric pathogens that significantly contribute to diarrhoeal disease worldwide. Like the murine pathogen Citrobacter rodentium (CR), EPEC and EHEC intimately bind to enterocytes. This is mediated by the injection of multiple type III secretion system effectors, which operate as an intracellular signalling network that modulates host processes and promotes infection progression and dissemination. This work was founded on the hypothesis that rational redesign of the effector network could enable the generation of a live attenuation vaccine (LAV) candidate that balances safety with immunogenicity. Using CR as a preclinical model, a minimal network consisting of only 10 of 31 effectors was generated, and named CRV (C. rodentium vaccine). CRV colonised C57BL/6 mice at levels ~100-fold lower that wild type (WT) CR. The presented work characterises this strain in both C57BL/6 and susceptible C3H/HeN mice to elucidate its infection profile, including histological phenotypes, immune cell infiltrates, cytokine profiles and protective potential. Comparative serological analyses between WT- and CRV-infected mice revealed an expanded antigenic landscape of CR infection, highlighting potential immune targets for vaccine refinement. In parallel, O-antigen-deficient mutants were evaluated in vivo to delineate the contribution of these surface polysaccharides to virulence. This work advances a new paradigm for attenuation, demonstrating that selective pruning of effector networks can yield safe and immunogenic live vaccines against A/E pathogens.
Version
Open Access
Date Issued
2025-10-26
Date Awarded
2026-06-01
Copyright Statement
Attribution-NonCommercial 4.0 International Licence (CC BY-NC)
License URL
Advisor
Frankel, Gad
Clements
Sponsor
President's PhD Scholarship Fund
Publisher Department
Department of Life Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)