Mechanism By which Oral Bacterium Causes Heart Disease Identified

Highlights

• Streptococcus gordonii is an oral bacterium that is an opportunistic pathogen that can cause a fatal heart condition called infective endocarditis.
• Adhesion of bacteria to host cells is important for their colonization and ability to cause disease.
• The research team identified a bacterial adhesin called CshA, which acts as a 'molecular lasso' enabling Streptococcus gordonii to bind to the surface of human cells and trigger the disease.

A key molecular process that occurs in the case of infective endocarditis (IE) has been revealed by researchers from the University of Bristol . IE is an infection of the lining of the heart caused by bacteria that gain access to the heart via bloodstream.

It can lead to unwanted blood clot formation. It is often overlooked or misdiagnosed and if untreated, it can result in fatal consequences.

Even after treatment the mortality rates remain high (up to 30%).

In the U.K, annually over 2,000 cases of infective endocarditis are diagnosed.

Researchers looked at the role of Streptococcus gordonii in causing IE, which normally resides in the oral cavity.

The human mouth can harbor more than 700 different species of bacteria.

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Under normal circumstances these organisms co-exist with the resident oral microbiota. But when bacteria spread to other tissues via the blood stream as in the case of IE, the results can be catastrophic.

Role of Protein CshA

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Previous studies have established that a protein called CshA playes an important role in targeting the oral bacterium Streptococcus gordonii to the tissues of the heart.

For the current study, researchers used the UK national synchrotron facility, Diamond Light Source.

Using this giant X-ray microscope the team were able to visualize the structure and dynamics of a protein called CshA.

The researchers found that CshA acts as a 'molecular lasso' which enables 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. This adhesions are facilitated by bacterial adhesins at the cell surface. CshA is one such bacteria adhesin which mediates binding to both host molecules and other microorganisms, is an important determinant of colonization by Streptococcus gordonii

Catch-Clamp Mechanism

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 terminal portion of CshA is very flexible which allows it to be cast out from the surface of the bacterium like a lasso.

In the catch-clamp mechanism, the 'catch' occurs when the lasso contacts a protein called fibronectin on the surface of human cells. The 'catch' 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 findings could lead to the development of new drugs to help combat this life threatening heart disease.

The study which was conducted in collaboration with Professor Rich Lamont at the University of Louisville, USA is published in the Journal of Biological Chemistry.

Reference

1. Infective Endocarditis - (http://patient.info/in/doctor/infective-endocarditis-pro)
2. Catherine R. Back et al. The Streptococcus gordonii adhesin CshA binds host fibronectin via a catch-clamp mechanism. Journal of Biological Chemistry; (2017)

Source-Medindia