A systems biology approach to understanding and combating Clostridium difficile infection.

The bacterium Clostridium difficile causes thousands of deaths every year in the United Kingdom through healthcare-associated infections. The impact upon the healthcare system is enormous and set to worsen due to the increasing prevalence of hypervirulent and antibiotic-resistant strains. An urgent need to develop novel therapies to tackle C. difficile infection thus exists. C. difficile infection is controlled by a complex network of genes that detects optimal conditions for a successful infection, regulating the production of toxins and the initiation of related mechanisms accordingly. The complexity of such nonlinear networks defies their understanding by a single discipline alone. This fellowship will provide the necessary microbiology training for crucial experimental work to be undertaken and, in tandem with computational models of these networks, a radical enhancement in our understanding of C. difficile infection will be achieved. Crucially, the models will capture conventional and novel therapies (the latter targeting toxin production directly), enabling hypotheses to be generated upon the relative effectiveness of these therapies and estimates made upon required dosages. Thus this interdisciplinary approach has the potential to improve health and longevity in the United Kingdom and worldwide, reducing the impact of C. difficile infection by accelerating the advancements of novel therapies.

Aims and objectives: The bacterium Clostridium difficile causes thousands of deaths every year in the United Kingdom through healthcare-associated infections. The impact upon the healthcare system is enormous and set to worsen due to the increasing prevalence of hypervirulent and antibiotic-resistant strains: an urgent need exists to further understand C. difficile infection and to develop novel therapies with which to combat it. Computational modelling will be employed to simulate gene regulation networks involved in toxin production and sporulation (crucial processes of C. difficile infection), providing hypotheses upon the associated gene, protein and signal interactions and generating the foundation for the experimental work. Combining experimental and theoretical work will uncover fundamental mechanisms behind the infection, its complexity defying its understanding by a single discipline. Experiments will test model-driven hypotheses, providing validation and parameterisation, and yielding reliable models into which current and future therapies can be incorporated, facilitating in silico prediction of the most effective therapies and required dosages. This interdisciplinary work has the potential to improve health and longevity in the United Kingdom and worldwide, reducing the impact of C. difficile infection by accelerating the advancements of novel therapies that target toxin production directly.
Design and methodology: Experimental work involving gene manipulation techniques and sequencing (ClosTron, RNA-Seq) will take place in months 12-16, 21-24 and 29-32, and will be closely integrated with the theoretical work. A modular framework is proposed for the modelling, comprising gene regulation networks involved in (i) toxin production (months 1-12) and (ii) sporulation (months 5-16), with the final module being (iii) anti-infection therapies (months 17-36); experimental work is restricted to (i) and (ii). The modules will be coupled together to form a comprehensive profile of C. difficile infection and the efficacies of a range of therapies and will involve deterministic (ordinary and partial differential equations) and stochastic (master and Langevin equations) approaches, numerical solution methods and multiscale asymptotic methods for model reduction and analysis. Collaborative visits to the Dupuy laboratory at the Institut Pasteur, Paris, are scheduled in the first and final years for model and experiment development and for discussion and dissemination of results.
Scientific opportunities: Theoretical, technical and practical modules of the MSc in Molecular Medical Microbiology will be undertaken at the University of Nottingham (months 5-16) to gain expertise in microbiology laboratory work, facilitating a truly interdisciplinary approach to tackling the biomedical problem of C. difficile infection and informing the applicant‘s subsequent research career.