How bacteria exploit proteins to trigger potentially lethal infections

Posted on 2 May 2014

New research by scientists at the University of York sheds light on how bacteria exploit human proteins during infections.

A research team led by Professor Jennifer Potts, a British Heart Foundation Senior Research Fellow in York’s Department of Biology, studied how Staphylococcus aureus, which can cause life-threatening human infections, attach to two proteins fibronectin and fibrinogen found in human blood.

The human proteins play important roles in clot formation and wound healing and the bacteria appear to exploit them during the process of infection.

Scientists had earlier shown that the binding sites for fibrinogen and fibronectin on the S. aureus protein FnBPA appear to “co-operate” in causing the dangerous heart infection infective endocarditis and the latest research suggest how the process occurs. The researchers, who included Vaclav Stemberk and Dr Richard Jones at York and Dr Ruth Massey, a microbiologist at the University of Bath, used X-ray crystallography, biophysical techniques and bacterial assays to investigate the process.

In research published in the Journal of Biological Chemistry, they solved the three dimensional structure of the bacterial protein FnBPA in complex with a small part of the human protein fibrinogen. This work showed that the fibrinogen binding site on FnBPA is close to, but not overlapping with, the binding site for fibronectin.

They then studied the binding of the two human proteins simultaneously to FnBPA and found that binding of fibronectin appears to block binding of fibrinogen to the bacterial protein. It appears that regulation of binding arises due to the close proximity of the fibrinogen and fibronectin binding sites on the bacterial protein and the large size of the human proteins. While the research provides the first biophysical evidence in support of the co-operation previously observed in the infection studies, it is still not clear how these two observations are linked. The scientists are planning further studies.

Professor Potts said: “Bacteria have evolved various mechanisms to exploit human proteins to cause infection. Understanding these mechanisms might not only lead to the development of new therapeutics but can also provide important information regarding the normal role of these human proteins in the body.”

Dr Sanjay Thakrar, Research Advisor at the British Heart Foundation, which co-funded the study, said: “The bacteria studied can cause a wide range of infections including the potentially fatal heart infection known as infective endocarditis.

“This study showed how this bacterium interacts with proteins found in our blood, which may give us an insight into how these deadly heart infections occur. This is an important step towards developing new treatments, but more research is needed to fully understand this interaction.”

The research was supported by the British Heart Foundation and the Biotechnology and Biological Sciences Research Council.

Further information:

The paper ‘Evidence for Steric Regulation of Fibrinogen Binding to Staphylococcus aureus Fibronectin-binding Protein A (FnBPA)’ is published in the Journal of Biological Chemistry. www.jbc.org/content/early/2014/03/11/jbc.M113.543546.abstract
For more information about the Department of Biology at the University of York, please visit http://www.york.ac.uk/biology/
British Heart Foundation: Coronary heart disease is the UK’s single biggest killer. For over 50 years we’ve pioneered research that’s transformed the lives of people living with heart and circulatory conditions. Our work has been central to the discoveries of vital treatments that are changing the fight against heart disease. But so many people still need our help. From babies born with life-threatening heart problems to the many Mums, Dads and Grandparents who survive a heart attack and endure the daily battles of heart failure. Join our fight for every heartbeat in the UK. Every pound raised, minute of your time and donation to our shops will help make a difference to people’s lives. For more information visit bhf.org.uk
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, and with an annual budget of around £467M (2012-2013), 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 see www.bbsrc.ac.uk