Bacterium lassoes its way from the mouth to the heart to cause disease
Press release issued: 7 February 2017
The human mouth can harbour more than 700 different species of bacteria. Under normal circumstances these microbes co-exist with us as part of our resident oral microbiota. But when bacteria spread to other tissues via the blood stream, the results can be catastrophic.
Researchers from the University of Bristol have now revealed a potentially key molecular process that occurs in the case of infective endocarditis, a type of cardiovascular disease in which bacteria cause unwanted blood clots to form on heart valves. If untreated, this condition is fatal and even with treatment, mortality rates remain high (up to 30 per cent). There are over 2,000 cases of infective endocarditis in the UK annually and the incidence is rising.
The Bristol team’s findings could lead to the development of new drugs to help combat this life threatening heart disease.
A key part of the study involved use of the UK national synchrotron facility, Diamond Light Source. Using this giant X-ray microscope the team were able to visualise the structure and dynamics of a protein called CshA which, based on previous studies at Bristol University, was believed to play an important role in targeting the oral bacterium Streptococcus gordonii to the tissues of the heart. The researchers were intrigued to find that CshA acts as a ‘molecular lasso’ to enable S. gordonii to bind to the surface of human cells. Such adhesive interactions are critical first steps in the ability of this bacterium to cause disease.
Lead author Dr Catherine Back from Bristol’s School of Oral and Dental Sciences, said: “What our work has revealed is a completely new mechanism by which S. gordonii and related bacteria are able to bind to human tissues. We have named this the ‘catch-clamp’ mechanism.”
The team were able to demonstrate that the terminal portion of CshA is very flexible. This allows it to be cast out from the surface of the bacterium like a lasso. When the lasso contacts fibronectin on the surface of human cells (the ‘catch’), it brings CshA and fibronectin into close proximity. This then enables another portion of CshA to tightly ‘clamp’ the two proteins together, anchoring S. gordonii to the host cell surface.
Co-researcher Dr Paul Race from Bristol’s School of Biochemistry and the BrisSynBio Research Centre, said: “What is particularly exciting about this work is that it opens up new possibilities for designing molecules that inhibit either the ‘catch’ or the ‘clamp’ steps in this process, or potentially both. The latter possibility is particularly intriguing, as bacteria are generally less likely to become resistant to agents that target multiple steps in an infective process.”
Dr Angela Nobbs, from the School of Oral and Dental Sciences, who co-led the study with Dr Race, added: “With the molecular level insight that our study provides, it is now a realistic possibility that we can begin to develop anti-adhesive agents that target disease-causing Streptococcus and related bacteria.”
The research was funded by grants from the National Institutes of Health (NIH) and the Biotechnology and Biological Sciences Research Council (BBSRC).
‘The Streptococcus gordonii adhesin CshA binds host fibronectin via a catch-clamp mechanism’ by Catherine R. Back et al in Journal of Biological Chemistry
About the National Institutes of Health (NIH)
NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
The Biotechnology and Biological Sciences Research Council (BBSRC) invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.
Funded by Government, BBSRC invested over £509M in world-class bioscience in 2014-15. We support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.
For more information about BBSRC, our science and our impact see: http://www.bbsrc.ac.uk
For more information about BBSRC strategically funded institutes see: http://www.bbsrc.ac.uk/institutes