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

Lead Research Organisation: University of Birmingham
Department Name: School of Mathematics

Abstract

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.

Technical Summary

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.

Publications

10 25 50
 
Description JPI-EC-AMR Joint Transnational Call for Proposals 2016 "Transmission Dynamics of Antimicrobial Resistance"
Amount € 1,703,996 (EUR)
Funding ID MR/P028195/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2017 
End 02/2020
 
Description JPIAMR Working Group Call for proposals
Amount € 49,045 (EUR)
Organisation Joint Programming Initiative on Antimicrobial Resistance 
Sector Public
Country Sweden
Start 10/2016 
End 12/2017
 
Description MBI workshop: travel and participation award.
Amount £500 (GBP)
Organisation Ohio State University 
Sector Academic/University
Country United States
Start 02/2012 
End 03/2012
 
Description School of Mathematics, University of Birmingham, Doctoral Training Award 2014
Amount £41,500 (GBP)
Organisation University of Birmingham 
Department School of Mathematics
Sector Academic/University
Country United Kingdom
Start 10/2014 
End 09/2017
 
Description Wellcome Trust Institutional Strategic Support Fund - Best practice in mathematical model parametrisation for predictive medicine
Amount £14,150 (GBP)
Funding ID 1516ISSFFEL9 
Organisation Wellcome Trust 
Department Wellcome Trust Institutional Strategic Support Fund
Sector Charity/Non Profit
Country United Kingdom
Start 02/2016 
End 09/2016
 
Title ODE Model for Quorum Sensing 
Description Ordinary differential equation models of quorum sensing placed in a public online repository (JWSonline) in a machine readable format to encourage further analysis by other research groups and to make the models available to the general public. 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2011 
Provided To Others? Yes  
Impact Requests from other research groups for further information about the models. 
 
Title ODE model for resistance to C. difficile colonisation 
Description Ordinary Differential Equation model examining the mechanisms by which the gut is usually resistant to C. difficile colonisation, to try and understand how resistance can be restored in a gut that has been disrupted by antibiotic use. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2015 
Provided To Others? Yes  
Impact Collaborations have been instigated with a number of theoretical and experimental groups in the USA. 
 
Title ODE model for toxin production 
Description Mathematical (ordinary differential equation) model of toxin production by Clostridium difficile. Used to analyse the bacteria in silico. 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2012 
Provided To Others? Yes  
Impact This research material has resulted in a collaborative publication with experimentalists at the University of Nottingham. 
 
Title Time-series RNAseq data of C. difficile 
Description Time-series RNAseq data of C. difficile 630 for mathematical model parameterisation 
Type Of Material Biological samples 
Provided To Others? No  
Impact The data will facilitate model parameterisation, in addition to yielding insight into the dynamics of gene regulation in C. difficile 
 
Title ODE model of anti-virulence drugs as novel antibacterials 
Description An ODE model of anti-virulence drugs as novel antibacterials and how they can be used to combat the emergence of antibiotic-resistance during an infection. 
Type Of Material Computer model/algorithm 
Year Produced 2014 
Provided To Others? Yes  
Impact The model is available on ArXix, pre-publication. The model has generated interest from other international research groups, with whom we are working to further improve the model. The ODEs should lead to a joint publication with the Krachler laboratory in the Institute of Microbiology and Infection, University of Birmingham. 
URL http://arxiv.org/abs/1409.4238
 
Title ODE model of resistance to C. difficile colonisation 
Description ODE model of resistance to C. difficile colonisation combining competition with other bacteria and host bile acid mechanisms 
Type Of Material Computer model/algorithm 
Year Produced 2016 
Provided To Others? Yes  
Impact Future collaboration with Hermann Eberl, University of Guelph, Canada 
 
Title ODE model of the emergence of antibiotic resistance during an infection 
Description ODE model describing the emergence of antibiotic resistance during an infection 
Type Of Material Computer model/algorithm 
Year Produced 2014 
Provided To Others? Yes  
Impact The model is available on ArXix, pre-publication. The model has generated interest from other international research groups, with whom we are working to further improve the model. The ODEs should lead to a joint publication with the Krachler laboratory in the Institute of Microbiology and Infection, University of Birmingham. 
URL http://arxiv.org/abs/1409.4238
 
Description Blair lab 
Organisation University of Birmingham
Department Institute of Microbiology and Infection
Country United Kingdom 
Sector Academic/University 
PI Contribution Mathematical modelling of efflux pump regulation in salmonella.
Collaborator Contribution Experimental data and guidance for mathematical models of efflux pump regulation.
Impact We have a joint student working on this project.
Start Year 2017
 
Description Dupuy Laboratory 
Organisation Pasteur Institute, Paris
Country France 
Sector Academic/University 
PI Contribution I undertook a research visit to the Institut Pasteur in January 2012. I was able to promote mathematical modelling and an interdisciplinary approach to a microbiology audience.
Collaborator Contribution The Dupuy group were able to give me data and new (unpublished) information about the gene regulation networks of interest. These will feed directly into the models I generate.
Impact Publications resulting from this collaboration are in preparation. The collaboration is multidisciplinary: I have the mathematical modelling expertise and the Dupuy group have experimental microbiology expertise.
Start Year 2012
 
Description Henderson lab 
Organisation University of Birmingham
Department Institute of Microbiology and Infection
Country United Kingdom 
Sector Academic/University 
PI Contribution Statstical analysis of tradis data
Collaborator Contribution Generation of tradis data
Impact Multidisciplinary (microbiology, maths), paper published together.
Start Year 2014
 
Description JPIAMR network grant 
Organisation Goethe University Frankfurt
Country Germany 
Sector Academic/University 
PI Contribution I am the sole mathematical modeller named on a JPIAMR network grant on "Exploiting an old drug as a basis for new inhibitor discovery"
Collaborator Contribution Experimentalists and clinicians contributing to the network
Impact £49,000 network grant from JPI-AMR to develop applications for projects on "Exploiting an old drug as a basis for new inhibitor discovery"
Start Year 2016
 
Description JPIAMR network grant 
Organisation University of Birmingham
Country United Kingdom 
Sector Academic/University 
PI Contribution I am the sole mathematical modeller named on a JPIAMR network grant on "Exploiting an old drug as a basis for new inhibitor discovery"
Collaborator Contribution Experimentalists and clinicians contributing to the network
Impact £49,000 network grant from JPI-AMR to develop applications for projects on "Exploiting an old drug as a basis for new inhibitor discovery"
Start Year 2016
 
Description Krachler laboratory 
Organisation University of Birmingham
Department Institute of Microbiology and Infection
Country United Kingdom 
Sector Academic/University 
PI Contribution We supplied a student to model a microbiology problem that arose in their lab.
Collaborator Contribution Supply of microbiology information and detail surrounding the problem, guidance in the direction of the work.
Impact The work is multidisciplinary: microbiology and mathematical modelling. The collaboration resulted in a MSc report which will eventually be submitted for publication. It has also informed the direction of undergraduate microbiology research projects, and will form the basis of a research grant proposal in the future.
Start Year 2013
 
Description Lund laboratory 
Organisation University of Birmingham
Department Institute of Microbiology and Infection
Country United Kingdom 
Sector Academic/University 
PI Contribution We supplied a student to work on a modelling project that arose from some lab work performed in this group.
Collaborator Contribution Supply of data for modelling purposes
Impact Multidisciplinary: microbiology and mathematical modelling. The project generated a MSc Report which will eventually be submitted for publication in an interdisciplinary journal.
Start Year 2013
 
Description NIMBioS 
Organisation University of Tennessee
Country United States 
Sector Academic/University 
PI Contribution Mathematical modelling of Clostridium difficile using differential equations.
Collaborator Contribution Mathematical modelling using cellular automata and parameter sensitivity analyses.
Impact Attendance at A Research Collaboration Workshop for Women in Mathematical Biology
Start Year 2015
 
Description Piddock lab 
Organisation University of Birmingham
Department School of Sport, Exercise and Rehabilitation Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution I have a PhD student, George Youlden, working on mathematical modelling of gene regulation networks governing antibiotic resistance, in collaboration with Laura Piddock.
Collaborator Contribution Laura Piddock's group are providing invaluable experimental data and advice about the underlying biology.
Impact Multi-disciplinary PhD student, George Youlden, based in the School of Mathematics but working alongside the Institute of Microbiology and Infection
Start Year 2016
 
Description Theriot Lab 
Organisation University of North Carolina at Chapel Hill
Country United States 
Sector Academic/University 
PI Contribution Mathematical modelling of resistance to Clostridium difficile colonisation.
Collaborator Contribution Exerimental data to parameterise mathematical models of resistance to Clostridium difficile colonisation.
Impact Attendance at National Institute for Mathematical and Biological Synthesis' Research Collaboration Workshop for Women in Mathematical Biology at the University of Tennessee (June 22nd-25th 2015). Collaboration is multi-disciplinary - mathematical modelling and practical microbiology.
Start Year 2015
 
Description Association for Science Education Conference 2014, 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Teachers attended a presentation about using mathematical modelling to develop novel drugs. There was much discussion following the presentation.

I was invited to write an article about my research for the Society of Biology's magazine The Biologist
Year(s) Of Engagement Activity 2014,2019
URL http://www.ase.org.uk/conferences/previous-annual-conferences/ase-annual-conference-2014/
 
Description British Science Festival workshop 2014 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Schools
Results and Impact 6th form students attended an interactive workshop entitled "Using maths to survive the zombie apocalypse". This introduced them to the idea of mathematical modelling in medicine and I used real-life examples from my reseach to show how maths can be used in the development of novel antibacterial drugs.

Many students stated that though they didn't really enjoy maths at school, that they really enjoyed the workshop.
Year(s) Of Engagement Activity 2014
URL http://www.britishscienceassociation.org/british-science-festival/birmingham-2014
 
Description Cafe Scientifique 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact 02/10/18 I was invited to participate in a Cafe Scientifique event at Pure Bar Birmingham, to discuss my research with general members of the public
Year(s) Of Engagement Activity 2018
URL http://www.cafescientifique.org/index.php?option=com_contentbuilder&controller=details&id=1&record_i...
 
Description Invited article for The Biologist 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited article about mathematical modelling in biology to a readership of over 14,000 members.

I have been approached by biologists to say how interesting they thought the article was.
Year(s) Of Engagement Activity 2014
URL https://thebiologist.societyofbiology.org/index.php/biologist
 
Description MRC Max Perutz Award 2013 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I wrote an entry for the MRC Max Perutz Science Writing Award.

I am likely to use the article in our university/college magazine.
Year(s) Of Engagement Activity 2013
 
Description MRC Max Perutz award 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Type Of Presentation Paper Presentation
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact I wrote an entry for the MRC Max Perutz Science Writing Award which was longlisted ("The latest antibacterial weapon: mathematics").

I will partake in science writing events in the future.
Year(s) Of Engagement Activity 2012
 
Description Mayfest, Nottingham 2012 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Schools
Results and Impact The University of Nottingham hold an event annually called Mayfest. It as in open day for all ages, designed to promote ongoing research within the university. I designed and hosted a number of games illustrating mathematical modelling of bacterial populations. Children of a range of ages participated in the games throughout the day.

Many of the older children discussed their A Level/university options with me.
Year(s) Of Engagement Activity 2012
 
Description Open Day Talks 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Popular Maths presentation on the university open day.

Our popular maths talks generate enthusiasm for maths and are thought to boost applicant numbers.
Year(s) Of Engagement Activity 2013,2014,2015
 
Description Popular Maths Evening Talk, School of Mathematics, University of Birmingham 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Popular Maths Evening Talk, School of Mathematics, University of Birmingham
50-100 pupils/teachers attending from local schools, sparked lots of discussion and questions
21st January 2015
17th February 2016

Contacted by student to be interviewed for his maths blog.
Year(s) Of Engagement Activity 2015,2016
URL http://www.birmingham.ac.uk/schools/mathematics/news-and-events/birmingham-popular-maths-lecture.asp...
 
Description School Talks 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Talk sparked lots of discussion, questions and positive reactions to how mathematics can be used to understand the world.

Cheltenham Ladies College 14/10/15
Sherborne Girls 06/11/15
King Edward VI Five Ways 06/10/16

Regularly invited to give more school talks. Events are usually held by independent schools, but local comprehensives are also always invited.
Year(s) Of Engagement Activity 2015,2016
 
Description The Training Partnership 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Schools
Results and Impact Presentations to up to 900 A level students each time about mathematical modelling in biology.

18/11/14, London Institute of Education
27/11/14, London Institute of Education
08/12/15, University of Warwick; 10/11/17 University of Salford; 15/11/17 University of Warwick;

Numerous invitations to present at schools and 6th form conferences including Sherborne School for Girls, the Gloucestershire branch of the Mathematical Association (held at Cheltenham Ladies College), Isle of Man Sixth Form Mathematics Symposium.
Year(s) Of Engagement Activity 2014,2015,2017
URL http://www.thetrainingpartnership.org.uk/
 
Description Year 12 Masterclasses 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact 6th form students attend an interactive workshop entitled "Using maths to survive the zombie apocalypse". This introduced them to the idea of mathematical modelling in medicine and I use real-life examples from my reseach to show how maths can be used in the development of novel antibacterial drugs. In 2017 we introduced an activity to document the change in attitude.

22/01/14
21/01/15
18/11/15
17/11/16; 01/11/17
21/11/18

We were invited to repeat the workshop the following year.
Year(s) Of Engagement Activity 2014,2015,2016,2017,2018
URL http://www.birmingham.ac.uk/undergraduate/advice/west-midlands-schools/Masterclasses.aspx