Abstract
Clostridium difficile infection is the primary cause of nosocomial diarrhoea in developed countries and the cost to healthcare providers is substantial. C. difficile is an opportunistic pathogen, with disease occurring when the normal colonic flora is disrupted. Dysbiosis of the intestinal microbiota, usually associated with antibiotic use, allows ingested spores of C. difficile to germinate and proliferate. Clinical symptoms are mediated by production of two major exotoxins, toxin A and toxin B. Clinical manifestations of infection can range from a non-symptomatic carrier state to diarrhoea and inflammation of the gut. Severe infections have potential to be fatal. Current treatment strategies for this infection rely heavily on just a few available antibiotics, as strains display multiple antibiotic resistances.
This thesis investigates the use of alternative treatment strategies, using Bacillus subtilis spores as a basis. One aspect of this assesses the use of B. subtilis spores as a mucosal vaccine delivery system. Delivery of a spore based vaccine by both oral and sublingual routes demonstrates these mucosal routes as promising strategies for generating protection against CDI. This thesis also uses B. subtilis spores as an oral probiotic treatment. The application of B. subtilis probiotics in a murine model of CDI is investigated and it is shown through optimisation of dose regimens that suppression of CDI symptoms can be achieved. Both use of vaccines and alternative treatments such as probiotics have the potential to reduce reliance on antibiotic treatment methods.
The role of C. difficile spores in infection was also investigated. Genetic manipulation was used to produce specific mutations in the spore coat and the resulting mutant phenotypes were analysed. This work demonstrated that the spore coat protein BclA1 plays a key role in colonisation of the host. This finding contributes to understanding how C. difficile can establish infection.
This thesis investigates the use of alternative treatment strategies, using Bacillus subtilis spores as a basis. One aspect of this assesses the use of B. subtilis spores as a mucosal vaccine delivery system. Delivery of a spore based vaccine by both oral and sublingual routes demonstrates these mucosal routes as promising strategies for generating protection against CDI. This thesis also uses B. subtilis spores as an oral probiotic treatment. The application of B. subtilis probiotics in a murine model of CDI is investigated and it is shown through optimisation of dose regimens that suppression of CDI symptoms can be achieved. Both use of vaccines and alternative treatments such as probiotics have the potential to reduce reliance on antibiotic treatment methods.
The role of C. difficile spores in infection was also investigated. Genetic manipulation was used to produce specific mutations in the spore coat and the resulting mutant phenotypes were analysed. This work demonstrated that the spore coat protein BclA1 plays a key role in colonisation of the host. This finding contributes to understanding how C. difficile can establish infection.
| Original language | English |
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| Qualification | Ph.D. |
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| Supervisors/Advisors |
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| Award date | 1 Feb 2015 |
| Publication status | Unpublished - 2015 |
