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A Clostridal Biology Network to Facilitate European-wide Medical Countermeasures and Commercial Exploitation

Final Report Summary - CLOSTNET (A Clostridal Biology Network to Facilitate European-wide Medical Countermeasures and Commercial Exploitation)

INTRODUCTION
Clostridia are a large and important group of bacteria, both medically and industrially:
• C. difficile is now one of Europe’s most important causes of hospital infection
• C. perfringens is causing devastation in the European poultry industry
• C. botulinum continues to fuel public concerns over its misuse by bioterrorists
• C. acetobutylicum offers hope in potential sustainable biofuel production
• C. sporogenes & C. novyi offer novel cures for treating cancer
Consequently there is an urgent need to better understand their basic biology; to counter the diseases they cause and exploit their potential benefits. Progress has so far been impeded by fragmented research efforts, poor communication between industry and academia, a lack of trained young clostridial researchers, and inadequate genetic technology.

OBJECTIVES
Developed by the University of Nottingham, revolutionary ClostTron technology uniquely allows systematic inactivation of genes to evaluate their function. Using this technology and pulling together the multidisciplinary expertise from 11 Centres of Excellence in Academia, Government and Industry, across 7 different EU states, CLOSTNET aims to solve these problems. Its objectives are two-fold:
1. Research - To embark on a massive, multifaceted, co-ordinated research programme using the revolutionary “ClosTron” technology to better understand the biology of Clostridia and consequentially exploit their strengths and weaknesses for the good of mankind.
2. Training - To provide 24 young researchers (fellows), 2 based at each Centre of Excellence with world class, state-of-the-art, multidisciplinary scientific and technological training.

BENEFICIARIES
The beneficiaries of the project were:
The University of Nottingham, UK (Professor Nigel Minton), who was grant holder and project coordinator, held two conferences and two workshops and trained 4 fellows.
The University of Exeter, UK (Professor Rick Titball), who trained two fellows.
The University of Rostock, Germany (Professor Hubert Bahl) who held one workshop and trained 3 fellows.
Technical University Munich, Germany (Professor Wolfgang Liebl) who held one workshop and trained 2 fellows.
The University of Helsinki, Finland (Dr Miia Lindström), whoc trained two fellows.
Institute of Public Health, Maribor, Slovenia (Professor Maja Rupnik), who trained 1 fellow.
Istituto Superiore di Sanita, Rome, Italy (Professor Paula Mastrantonio) who trained 2 felows.
CNRS, Marseilles, France (Professor Chantal Tardif) who held one workshop and trained 2 fellows.
Novartis Vaccines, Siena, Italy (Dr John Telford) who held one workshop and trained 2 fellows.
Metabolic Explorer, France (Professor Philippe Soucaille) who trained two fellows.
Unilever, UK (Dr Peter McClure) who trained two fellows.

WORK DONE
Throughout the four years of the project, September 2009 to August 2013 a total of 24 fellows have carried out topical research on various aspects of Clostridial Biology. Of those, 21 either have or will have attained PhDs within the next 12 months. Eight Network training events have taken place: ClosTron Workshop and Conference 1, at the University of Nottingham, (Dec 2010), Transcriptomics Workshop at the Technical University Munich (March 2011), Proteomics Workshop at the University of Rostock (Sept 2011), Vaccines Workshop at Novartis Vaccines, Siena, Italy (May 2012), Secretion Workshop at CNRS, Marseille (Sept 2012), Gene Technologies Workshop and Conference 2, at the University of Nottingham (March 2013).

MAIN RESULTS
Research:
During the course of the project a number of notable ‘first’ were achieved: (i) REGULATION - the first example of a negative repressor of botulinum neurotoxin was discovered in C. botulinum, as well as nine new quorum sensing systems involved in the regulation of the production of the biofuel butanol in C. acetobutylicum; (ii) SPORES - a C. difficile-specific mariner transposon system was used to isolate 22 random mutants with sporulation/germination defects, and then the system adapted through a number of technological innovations such that it could be universally applied in any Clostridium, and exemplified in C. acetobutylicum and C. sporogenes; (iii) SECRETION – immunological investigation of the C. perfringens NetB toxin led to the basis of a new vaccine, a lipoprotein produced by C. difficile was shown to play a role in virulence and a novel chaperone involved in cellulosome secretion discovered in C. cellulolyticum; (iv) METABOLISM - In C. acetobutylicum the generation of ClosTron mutants in the solventogenic pathway has provided new insights into metabolic flux and shown that all hemicellulases of C. cellulolyticum growing on straw are produced under the control of a two-component response regulator XydR, and; (v) GENOMES – The fitness cost of antibiotic resistance through mutation or via the acquisition of mobile elements was determined and the first evidence that C. difficile forms biofilms was obtained, a phenotype that was affected by naturally occurring SNPs in the genome.
Training:
Fellows have attended a total of 170 courses and 128 conferences. They have presented 100 posters and 96 talks and have 25 papers published or pending. 11 have demonstrating experience and/or have supervised MSc students, 15 have had secondments, 2 organised a Network workshop for 33 delegates and one organised a research symposium for 150 delegates.

CONCLUSIONS, POTENTIAL IMPACT AND USE
CLOSTNET has promoted women in science (57% recruitment) and has recognised the untapped potential of less favoured and newly associated EU States and developing countries. Using this talent, CLOSTNET has created of a network of new clostridial researchers who, armed with ClostTron technology and their own scientific outputs will increase the competitiveness and innovative capacity of European institutes and industries, leaving them poised to supply the world with knowledge and products, creating jobs and wealth.
CLOSTNET will lead to the improvement of the health of European citizens by providing better diagnostic tests, therapeutic drugs and vaccines against healthcare associated infections, providing novel cancer treatments and helping farmers improve food quality and supply. Most excitingly, CLOSNET will address environmental issues with the development of a superior Biofuel to help overcome EU reliance on fossil fuels and reduce its Carbon emissions.

CONTACT
Professor Nigel Minton (Project Coordinator)
Centre for Biomolecular Sciences
University of Nottingham
University Park
Nottingham
NG7 2RD
tel: +44(0)115 846 7458
email: nigel.minton@nottingham.ac.uk
website: http://www.clostridia.net/clostnet/index.html