New paper: PVL toxin associated with pyomyositis


In a new collaborative study published this week in eLife, we report a strong association between Staphylococcus aureus that carry the PVL toxin and pyomyositis, a muscle infection often afflicting children in the tropics.

Catrin Moore and colleagues at the Angkor Children's Hospital in Siem Reap, Cambodia, spent more than a decade collecting S. aureus bacteria from pyomyositis infections in young children, and built a comparable control group of S. aureus carried asymptomatically in children of similar age and location.

When Bernadette Young in our group compared the genomes of cases and controls using statistical tools we developed, she found some strong signals:

  • Most, but not all, pyomyositis was caused by the CC-121 strain, common in Cambodia.
  • The association with CC-121 was driven by the PVL toxin which it carries.
The ability to pinpoint the association to PVL came about because (i) a sub-group of CC-121 that lacked PVL caused no pyomyositis and (ii) pyomyositis-causing S. aureus from backgrounds that rarely caused pyomyositis were unusual in also possessing PVL.

The strength of the PVL-pyomyositis association was extraordinarily strong, so strong that PVL appeared all-but necessary for disease. Moreover, disease appeared to be monogenic, with no other genes involved elsewhere in the bacterial genome. To discover an apparently monogenic disease mechanism for a common disease is very unusual nowadays.

The discovery has immediate practical implications because it draws parallels between pyomyositis and toxin-driven bacterial diseases like tetanus and diphtheria that have proven amenable to immunization. The fact that anti-PVL vaccines have already been developed in other contexts offers hope for the future treatment of this debilitating tropical infection.

Our study throws much-needed light on a subject that has been the subject of heated debate over previous years. Many bacterial toxins, PVL included, have been implicated in diverse S. aureus disease manifestations, often without sound evidence. Because PVL is known to contribute to angry, pus-filled skin infections, and has been observed in bacteria causing rare and severe S. aureus infections, some authors have implicated it in dangerous diseases including necrotizing pneumonia, septic arthritis and pyomyositis, but detailed meta-analyses have dismissed these claims as not substantiated. Our GWAS approach offers unprecedented robustness over previous generations of candidate gene studies by accounting for bacterial genetic variation across the entire genome.

If you are interested, please take a closer look at the paper.

The group has moved to the Big Data Institute, University of Oxford

From April we have moved to the Big Data Institute, Nuffield Department of Population Health at the University of Oxford. The group is maintaining its close links to the Modernising Medical Microbiology Consortium and the John Radcliffe Hospital, Oxford. I am grateful to the Robertson Foundation for funding. We're excited about joining new colleagues and benefiting from their expertise in epidemiology, health informatics, genetics and infection, while continuing to cultivate strong links with our existing collaborators in Oxford and around the world.

Prize PhD Studentships available

I am offering two PhD projects as part of the annual Nuffield Department of Medicine Prize Studentship competition:
These are fully-funded, four-year awards open to outstanding students of any nationality. Applicants nominate three projects, in order of preference, from the available pool. For how to apply, click here. Only applications submitted through the online system will be considered, but interested applicants are welcome to contact me informally. The deadline for applications is noon, 6th January 2017.

In addition to my projects, the Modernising Medical Microbiology project has announced the following PhD projects as part of the competition:

    CRyPTIC: rapid diagnosis of drug resistance in TB

    The Modernising Medical Microbiology consortium has announced a new worldwide collaboration called CRyPTIC to speed up diagnosis of antibiotic resistant tuberculosis (TB).

    TB infects nearly 10 million people each year and kills 1.5 million, making it one of the leading causes of death worldwide. Almost half a million people each year develop multidrug-resistant (MDR) TB, which defies common TB treatments. Time consuming tests must be run to identify MDR-TB and which drugs will work or fail. This delays diagnosis and creates uncertainty about the best drugs to prescribe to individual patients.

    CRyPTIC aims to hasten the identification of MDR-TB using whole genome sequencing to identify genetic variants that give resistance to particular drugs. The project is funded by a $2.2m grant from the Bill & Melinda Gates Foundation and a £4m grant from the Wellcome Trust and MRC Newton Fund.

    CRyPTIC aims to collect and analyse 100,000 TB cases from across the world, providing a database of MDR-TB that will underpin diagnosis using WGS. Samples from across Africa, Asia, Europe and the Americas will be collected by teams at more than a dozen centres They will conduct drug resistance testing and much of the genome sequencing. Read more information here.

    The role of hospital transmission in Clostridium difficile infection

    This week the Modernising Medical Microbiology consortium at Oxford published the findings of a six-year study into the transmission of the hospital "superbug" Clostridium difficile. The research, which appears in the New England Journal of Medicine, shows that the majority of new cases cannot be traced to other infections in hospital, and indicates instead that there must be a large, as yet unidentified, reservoir of C. difficile infectious to humans. This finding is important because it suggests that there is a limit to which more and more intense hospital cleaning - important though it has been - can continue to have in reducing C. difficile infection.

    The research, which is the result of a tireless effort by a large number of my colleagues - notably David Eyre, Tim Peto and Sarah Walker - used bacterial whole genome sequencing to detect within-hospital transmission by searching for extremely closely related bacterial strains among more than 1200 cases of C. difficile infection that occurred in Oxfordshire between September 2007 and March 2011. The consortium is currently developing the approach for routine microbiology diagnostics and infection control, with a view to eventual roll-out across the NHS.

    Postdoctoral Positions in Pathogen Genomics

    These positions are now closed. There are currently seven posts advertised to join the Pathogen Genomics group at the Nuffield Department of Medicine in Oxford. Prof Derrick Crook and colleagues are seeking exceptional, creative, quantitatively minded scientists to join a multidisciplinary team of researchers using population genomics to understand the evolution and transmission of human pathogens. We are seeking to appoint a number of promising young researchers to extend our existing strengths in the areas of phylogenomics, statistical genetics and bioinformatics.

    The group is studying a range of bacterial and viral pathogens including tuberculosis, Staphylococcus aureus, Clostridium difficile, HIV, norovirus and hepatitis C virus. Our research interests include within-host evolution, the genetic basis of virulence, transmission dynamics and outbreak investigation via real-time genomics.

    A major translational goal of the project is to exploit the transformative effect of population genomics on bacteriology to improve routine clinical practice in public health and microbiology laboratories.

    The research is supported by the UKCRC Modernising Medical Microbiology Consortium, the Health Innovation Challenge Fund, the NHS National Institute for Health Research, the Oxford Biomedical Research Centre, Institut Merieux and the Oxford Martin School, and pursued in collaboration with clinical colleagues in Leeds, Birmingham and Brighton, the Health Protection Agency and the WTSI.
    The deadline for applications varies by position, between 26-28 November 2012.
    For examples of recent papers see:
    http://www.thelancet.com/journals/laninf/article/PIIS1473-3099%2812%2970277-3/fulltext
    http://www.pnas.org/content/109/12/4550.full
    http://bmjopen.bmj.com/content/2/3/e001124.full.pdf+html
    http://www.nature.com/nrg/journal/v13/n9/pdf/nrg3226.pdf
    http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1002874

    For more information visit:
    http://www.modmedmicro.ac.uk
    http://www.oxfordmartin.ox.ac.uk/projects/view/127

    James Martin Fellowship

    This position is now closed. A prestigious James Martin Fellowship funded by the Oxford Martin School is available in my research group for a highly motivated and creative population geneticist interested in developing cutting edge methods for the analysis of high-throughput whole genome sequencing data to better understand the evolution and epidemiology of the major pathogens HIV and Hepatitis C Virus.

    The position, which is part of the Curing Chronic Viral Infections project, is fully funded for three years and is affiliated with the Institute for Emerging Infections, the Modernising Medical Microbiology consortium, the Peter Medawar Building for Pathogen Research and the Nuffield Department of Medicine. The ideal candidate will have a track record in statistical or computational genetics and experience of programming in a language such as C++ or Java.

    Full details can be found on the University of Oxford Recruitment website. Please send informal enquiries, with a CV, to me by email. The deadline for applications is 12 noon on 27th November 2012.

    PNAS paper on staphylococcal evolution during infection

    Today in PNAS Early Edition my colleagues and I have a paper published reporting the genome evolution of Staphylococcus aureus during the transition from prolonged nasal carriage to invasive disease. Since Staph. aureus, a major bacterial cause of life-threatening infections, is carried without symptoms by a quarter of healthy adults, a natural question is to ask what genetic changes - if any - accompany the transition to invasive disease. The opportunity to pursue this question arose from a detailed epidemiological investigation of asymptomatic Staph. aureus nasal carriage set up by colleagues of mine including Derrick Crook and Kyle Knox. The study has recruited over 1,000 participants in Oxfordshire since it began running in October 2008. One participant developed a bloodstream infection that was indistinguishable from the strain of Staph. aureus persistently carried in the nose for the previous 13 months. Members of the Modernising Medical Microbiology consortium, led by Derrick and Rory Bowden, sequenced the genomes of 68 bacterial colonies isolated from the nasal and blood samples from this participant, and 101 colonies from nasal samples from two other participants that did not go on to develop disease. Bernadette Young and Tanya Golubchik analyzed the genome evolution of these bacterial populations, discovering an unusual pattern in the mutations that occurred between nasal carriage and invasive disease: mutations that led to prematurely truncated proteins were significantly over-represented, including one in a gene previously associated with virulence in bacteria. To know more, read the full open access article.