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Rationale

Three key areas continue to challenge modernising medical microbiology and infectious diseases: detecting and managing outbreaks, identifying microbial pathogenic factors which cause specific disease manifestations, and understanding the contribution of human host susceptibility factors to transmission and disease. Traditional phenotype-based typing has been a powerful aid in the recognition and supervision of infectious disease outbreaks. However, its utility for changing clinical management and focussing public health interventions, both in hospitals and the community, has been limited by its failure to generate sufficiently rich near-to-real-time data. Molecular epidemiological studies have also been limited by weak choice of sampling frames which are poorly representative of the underlying population biology and epidemiology, inadequate phenotype definitions, and lack of control for complex interactions between organism, host and environment.

Microbiology and infectious diseases research is being revolutionised by the following advances:

1. rapidly developing high-throughput technologies making fast, large-scale whole genome sequencing of pathogens cheap and feasible
2. superior processing approaches based on improved analytical algorithms and increased computational power
3. recognition that "high value" genetic regions, incorporating much of the informative diversity within a population, can be identified and sequenced
4. sophisticated web-based databases for secure direct linking of complex sequence and epidemiological data for distributed users.

These automated technologies dramatically change the speed with which samples can be processed, data analysed and results reacted to. The challenge is to harness next generation sequencing of complete pathogen genomes and informatics to address the key areas described above, and translate their greater speed and specificity into improvements in national surveillance and routine laboratory/clinical practice and public health in the field of microbiology across the UK.

Objectives

Specific primary objectives of this consortium are:

1. at a national level, to rapidly detect and track the spread of new epidemic strains
2. at a local level, to identify hitherto unrecognised outbreaks within an endemic setting, by using next generation sequencing of complete pathogen genomes, coupled with carefully defined population-based sampling frames
3. at an individual patient level, to recognise and follow outbreaks early enough to intervene effectively
4. to develop web-accessible informatics tools which are attractive and easy-to-use, enabling local practitioners to direct their routine infection control practice efficiently; but which are based on a platform that is flexible enough to add further types of data, scaleable for implementation across UK NHS service, and modular, to allow changes that can enable generalisation across the whole range of infection surveillance.

Themes and Collaborators

We are focusing on 4 different major pathogens that represent the spectrum of difficulty expected for infecting organisms, providing a balance of diverse challenges, different underlying research questions, and varying potential. The pathogen samples and clinical data are currently being collected throughout the UK through the HPA (Birmingham, London, Leeds and Brighton) and in Oxford through the Oxford University Hospitals NHS Trust. Listed in increasing complexity the pathogens are:

• Mycobacterium tuberculosis, a relatively rare human restricted pathogen evolving through descent
• Norovirus, a rapidly mutating RNA virus and common pathogen causing outbreaks
• Clostridium difficile, a recently emerged, genetically diverse and predominantly hospital-associated pathogen
• Staphylococcus aureus, a common, ancient, recombining commensal that has co-evolved with humans

This UK CRC Modernsing Medical Microbiology project is a consortium drawing together the breadth of the HPA, OxBRC and the NHS, the research strengths of the University of Oxford in microbiology, epidemiology, population genetics, statistics, bioinformatics, genomics and informatics and the whole genome sequencing resources and services of the High-Throughput Genomics (HTG) group at the Wellcome Trust Centre for Human Genetics and the  Wellcome Trust Sanger Institute .