Within-host evolution of Staphylococcus aureus during asymptomatic carriage

Given its notoriety as one of the world's major causes of infection-related deaths, it may come as a surprise that one in three healthy adults carry the human pathogen Staphylococcus aureus in their noses without adverse effects. Indeed, most people carry the bacteria at some point in their lives. So carriage must be seen as the normal state of affairs in the human-S. aureus interaction, and by understanding this state better we can improve our understanding of why, in some people, the bacteria go on to cause life-threatening invasive disease.

This month sees publication of an investigation by my colleagues and me into the evolution of S. aureus during this normal healthy carriage state. The carriers in our study harboured populations of the bacteria that were very closely related but typically not identical, implying that the bacteria had evolved within the human body. The nose appears to be a microcosm of evolution for S. aureus, showing all the different types of genetic variation known at the species level within the noses of these individual carriers. For the most part, within-host evolution of the bacteria was very conservative, but certain proteins expressed on the surface of the bacteria and toxins secreted by the bacteria showed evidence of involvement in a host-pathogen arms race.

The paper, whose lead authors include Tanya Golubchik, Liz Batty, Derrick Crook and Rory Bowden, has received coverage on the EveryONE blog and F1000. I liked Gerald Pier's conclusion, made on the post-publication peer review website: "Given that about 30% of the world's seven billion-plus humans, and an unknown number of animals, are chronically colonized with S. aureus, the tremendous opportunity provided to this organism for generating genetic variation to counteract human efforts to prevent S. aureus infections may be one of the most formidable barriers to overcome in order to develop vaccines and highly effective interventions to lessen the impact of this organism on human and animal health."

Nature Reviews Genetics: Transforming Clinical Microbiology

My colleagues Xavier Didelot, Rory Bowden, Tim Peto, Derrick Crook and I have just published a review online ahead of print in Nature Reviews Genetics called Transforming clinical microbiology with bacterial genome sequencing.

You might also be interested to read a similarly themed review recently published by our friends at the University of Cambridge and Wellcome Trust Sanger Institute in PLoS Pathogens titled Routine use of microbial whole genome sequencing in diagnostic and public health microbiology.

These review articles follow hot on the heels of a pair of research articles published by our two groups: A pilot study of rapid benchtop sequencing of Staphylococcus aureus and Clostridium difficile for outbreak detection and surveillance in BMJ Open and Rapid whole-genome sequencing for investigation of a neonatal MRSA outbreak in the New England Journal of Medicine. The common thread is the impact of near-to-real-time whole genome sequencing on outbreak detection and other translational activities in hospitals and public health laboratories.

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.

Evolutionary Genetics for Translational Research

This month saw the 2010 Infectious Disease Genomics & Global Health meeting at Hinxton, which attracted a good number of people involved in the Modernising Medical Microbiology consortium, of which I am a participant. Rory Bowden and Rosalind Harding presented our group's progress on piecing together intra-host evolution of Staphylococcus aureus and reconstructing transmission chains in Clostridium difficile. My role in the projects has so far been one of assisting in ongoing evolutionary analyses and collaborating in the design of bioinformatics pipelines to make sense of the raw Illumina short-read sequencing data. At the same time I have been devising research plans for my own group, and spending time in the lab preparing sequencing experiments with Bernadette Young. In the poster I presented at Hinxton (available here), and at an internal talk I gave earlier in the year (slides here) I set out what I see as the strengths of Evolutionary Genetics for addressing translational medical problems including

• Tracking the transmission of hospital-acquired pathogens
• Understanding transmission dynamics at the population level
• Identifying the mechanistic and adaptive basis of disease
• Explaining how pathogens emerge, persist and spread globally

Of the many stimulating talks at the Hinxton conference, those by Dominic Kwiatkowski on the population genomics of Plasmodium falciparum, Christophe Fraser on "hyper-recombination" in Streptococcus pneumoniae and Paul Keim on the challenges for understanding the population genetics of non-clonal bacterial pathogens particularly interested me. Prof Keim gave an equally captivating talk the following day at the Health Protection 2010 meeting in Warwick on his microbial forensics work tracing the origin of Bacillus anthracis spores used in bioterrorism attacks. What I especially admired about his presentations was the dogged pursuit of new methods and ways of thinking in order to better address the biological questions at hand.