MODERNISING MEDICAL MICROBIOLOGY: ESTABLISHING HOW NEW TECHNOLOGIES CAN BE OPTIMALLY INTEGRATED INTO MICROBIOLOGY

Successful control of infectious diseases depends on completely understanding how they are transmitted. The major challenges posed by tuberculosis, MRSA and hospital acquired diarrhoeas (C. Difficile and norovirus) would be easier to tackle if we could recognise individual outbreaks of infection with different strains. However, current typing schemes, which try to classify how different bugs are related to each other, are too slow and inadequate to reliably do this.

High-throughput sequencing of the human genome has revolutionised scientific research. We intend to exploit these advances to improve infectious diseases clinical practice. We will systematically collect strains of four pathogens from major UK hospitals and the clinical details of each case. The genomic techniques will allow us to precisely type large numbers of isolates so that we can track individual local outbreaks even if the bugs are very closely related. Better descriptions of routes of transmission will identify where guidelines for infection control can be improved. We will then develop rapid typing techniques so that infection outbreaks can be recognised and followed in real-time, and then successfully interrupted in a rational way. We will develop a web-based computer database so that a single system can be used across the country.

Three areas continue to challenge medical microbiology: detecting and managing outbreaks, identifying microbial pathogenic factors causing specific disease manifestations, and understanding the contribution of human host susceptibility. Ongoing advances in sequencing, bioinformatics and web-based technologies have now reached a stage where their potential for revolutionising the way we characterise microbes and investigate human disease can be envisaged. The real challenge is to harness and translate this potential into clinical practice and public health.

The goal of this Consortium is therefore to transfer new and established sequencing technologies into effective everyday public health and clinical microbiology practice.

Specific primary objectives are (i) at a national level, to rapidly detect and track the spread of new epidemic strains (ii) at a local level, to identify hitherto unrecognised outbreaks within an endemic setting, by coupling more discriminatory sequence typing with carefully defined sampling frames (iii) at an individual patient level, to recognise and follow outbreaks early enough to intervene effectively (iv) to develop attractive, easy-to-use web-accessible bioinformatics tools enabling local practitioners to direct routine infection control practices efficiently. Our secondary objective is to enable future population-based studies of microbial pathogenic factors and host genetically-determined susceptibility by assembling isolate collections and matched human DNA.

Our strategy focuses on four major pathogens providing diverse challenges and varying potential for successful application. We will use ultra-fast whole genomic sequencing to identify regions of informative diversity to augment established and lower resolution typing schemes, and to achieve sufficient power to detect transmission even of highly prevalent pathogenic strains. Rigorous population-based sampling frames appropriate for each organism will be defined, relevant clinical/epidemiological data collected, and infecting organisms and host DNA archived. Improved typing schemes will be implemented using established sequencing platforms, and outputs integrated in a single web-based environment for reporting and analysis. This should deliver near-real-time data-driven national surveillance and local clinical decision making, and could be integrated into the HPA Regional Microbiology Network (RMN).

To realise our scientific goal we will draw together the breadth of the HPA RMN, research strengths of the University of Oxford, and the sequencing/informatic resources of the Wellcome Trust Sanger Institute, enhancing training opportunities and leadership development in cutting-edge technologies for a large pool of microbiologists. UK capacity will be strengthened by creating a novel partnership with national reach, nurturing research trainees, developing practical software and analytical tools and assembling large well-defined sample archives.