Centre for Molecular Bacteriology and Infection

Bacterial infections continue to cause immense human suffering and mortality throughout the world. The incidence of some 'old' diseases such as tuberculosis has risen dramatically in recent years and important new infections have emerged. We lack efficacious vaccines for many bacterial diseases and the alarming worldwide rise in antibiotic-resistant bacterial pathogens continues unabated.

Surprisingly, despite its importance, there are no centres of excellence focussing exclusively on bacterial infection research (either in the UK or overseas) and there is a widespread concern about the shortage of UK-trained academics and clinicians developing research careers in bacterial infection biology. The Centre for Molecular Microbiology and Infection (CMMI) at Imperial College London consists of eleven independent research teams all working on different aspects of bacterial infection. Over the last decade these teams have made major contributions to our understanding of the nature of bacterial virulence at the cellular, molecular and structural levels.

The purpose of this application is to take advantage of exciting recent progress in bacterial infection biology to strengthen our current research portfolio and expand our interests to tackle important under-researched subjects that are complementary to our ongoing work. To achieve this, we wish to create an MRC-supported Centre for Molecular Bacteriology and Infection (CMBI). Imperial College will contribute by making available six new lectureship posts to study issues such as persistence and antibiotic resistance in bacterial pathogens in hospitals, host immune mechanisms and bacterial strains that cause disease in the developing world. To increase our ability to do leading edge research we are requesting new equipment and support posts from the MRC that will enable us to study the processes of infection and host responses in living tissues, and to purify and analyze important bacterial proteins at the molecular level. These studies will bring a deeper understanding of the processes that underlie bacterial pathogenesis and will suggest new approaches to develop anti-bacterial drugs and rationally designed vaccines against bacterial infections. The new Centre will have strong collaborations with academic, clinical and industrial colleagues outside the Centre who work on other aspects of bacterial disease, and with whom we can share expertise.

A very important element of this application is to take advantage of the excellent research environment and expertise within our Centre to provide basic science training in the form of PhDs. The training programmes offered by the CMBI will cover four major functions: (1) The training of academic bacterial infection biologists through a "1+3 year" combined MRes-PhD programme; (2) To enable students on the Imperial College six-year undergraduate medical course to undertake a 3 year MD-PhD in bacterial infection biology as part of their course; (3) To provide clinically qualified professionals (at specialty registrar level) with research training in bacterial infection biology through dedicated PhD training fellowships. This will provide clinical academics with the knowledge and analytical skills that will enable them to integrate basic science with practical medicine to pursue high quality and clinically relevant independent research in the field of bacterial infection biology.

Imperial College will provide six new lectureship posts to expand research capacity. Two posts are to study persistence and antibiotic resistance in nosocomial pathogens. One post is to study bacterial diversity in the developing world. Two posts are to study mechanisms of host immunity, bacterial discrimination and tolerance, and one post is to strengthen work on the structural biology of virulence proteins.

An underlying theme of the Centre is the study of molecular mechanisms of virulence proteins. However, progress in this area is slow and reliant on understanding protein structure. To accelerate work at atomic and cellular levels, we aim to establish a robotic Protein Production and Analysis Facility for high throughput purification and characterisation of important proteins and their complexes.

To follow the entire infection cycle of bacterial pathogens in small animals in real time using non-invasive techniques, we need an IVIS Spectrum-CT, a state-of-the-art instrument that combines computerised tomography with optical imaging and absolute photon quantification, allowing precise enumeration and location of infectious load. The instrument will be used to study the development of bacterial populations in vivo, the contribution of bacterial and host factors to bacterial colonisation and growth, and the effects of immunisation and antimicrobial treatments on the course of disease.

A major component of this proposal is to establish a "Centre of Excellence in Training" in bacterial infection biology. Our programmes will cover four major functions: (1) training bacterial infection biologists through an academic "1+3 year" combined MRes-PhD programme; (2) to enable students on the Imperial College six-year medical course to undertake a 3 year MD-PhD as part of their course; (3) to provide clinically qualified professionals with PhD research training in bacterial infection biology through fellowships.

The academic and clinical sectors will be the main beneficiaries of the CMBI: Firstly, the training programmes of the CMBI will produce a cohort of research scientists and academically trained clinicians who might develop their careers as infection biologists or move into different research fields. Secondly, the research themes in the CMBI will generate new theoretical and practical knowledge relevant to bacterial infection biology, and new resources (reagents, bacterial strains, experimental procedures etc.) that will benefit researchers in the immediate and wider field. Beneficiaries will be the large international research community that works on pathogenic bacteria, who will read papers published by CMBI researchers that could influence future research. Since some of the resources will be relevant to fundamental bacterial processes, beneficiaries will also include bacteriologists working on non-pathogenic bacteria. Clinical infectious disease specialists, structural biologists, immunologists, cell biologists, geneticists, vaccinologists and systems biologists will also be beneficiaries.

Industry: The industrial sector will be a long-term beneficiary of the CMBI. The existing and new research themes in the CMBI will generate knowledge that could inform new product development relevant to managing bacterial infections, and consequently stimulate development of appropriate delivery systems by the biomedical engineering sector. The usual channels of knowledge transfer will communicate results to the industrial sector (i.e. peer-reviewed publications, international and national conferences etc.). In addition, the proposed joint-industrial studentships will help establish new and foster existing links.

Society at large: Benefits to society at large will be twofold: In the short term, the CMBI will provide employment for several individuals at the postdoctoral level, thereby directly contribute to the national economy. We strive to become a "Centre for Excellence in Training" and as such our trainees are likely to benefit the UK healthcare system, biotechnology and pharmaceutical industries, as well as the academic base in the UK and its representation abroad. The research will improve our understanding of diseases caused by bacteria. Furthermore, the management of diseases caused by pathogenic bacteria has a costly impact on public health budgets (see CfS for further details). Outcome of research conducted in the CMBI could potentially inform novel interventions and strategies to manage infections caused by pathogenic bacteria, and ultimately contribute to improved public health, wellbeing and quality of life. Where appropriate, results will be communicated to the wider public via more readily accessible publications, e.g. through the media and popular science publications (see CfS for further details). Visits from local schools to see the "science in action" will be encouraged. To maximize the impact of these endeavors, we will seek advice from the Imperial College (IC) Communications Division, which incorporates Media Relations and Research Communications teams. The IC Institute for Global Health Innovation would provide another valuable vehicle for dissemination of new knowledge that may be generated by the proposed work. The IC Outreach Office offers a number of science outreach activities, which include, for e.g., Researcher in Residence scheme or Talk Science initiative with the Science Museum. These are excellent opportunities to engage school children and science teachers.

Government: One of the remits of the IC Institute for Global Health innovation is to translate new scientific knowledge into applications to improve global health by influencing international policy. When and where relevant, the CMBI will liaise with the IC Institute for Global Research Innovation to inform future health care policies based on our research activities.