Stuck on you: scientists lay bare secrets of bacterial attachment proteins

An unprecedented picture of how bacteria latch on to human cells has been published by UK, French and US scientists. They have produced a finely detailed model of one of the tools used by some of the nastiest varieties of the stomach bug, Escherichia coli, to stick to and gain entry to host cells.

Led by senior author Dr Stephen Matthews, Reader in Chemical and Structural Biology at Imperial College London, the research is published in the latest issue of the journal Molecular Cell (*See Notes to Eds).

Bacteria need to stick to a host cell, before colonising and attacking it, and causing infection. They do this with the help of proteins on their outer surface called adhesins and invasins. The former attaches itself to the host cell and the latter assists the invasion. Together they define how aggressive or virulent the bacteria are at attacking the host.

Most families of adhesins belong to bacteria that cause a single disease, but the ’Dr’ family of Adhesins makes far more trouble: it is responsible for chronic diarrhoeal, intestinal and urinary tract infections, and is similar to some present in strains of Salmonella.

The researchers characterised the way in which the Dr Adhesins help bugs to cause multiple diseases because they use a very common receptor on the host cell membrane as an anchor point to attack. They target a receptor responsible for regulating one of the important human immune responses, known as Decay Acceleration Factor, or DAF.

“Cell adhesion is one of the first contacts between bacteria and host,” said Dr Matthews. “Knowing the architecture of the bacteria target allows us to conceive ways to disrupt this adhesion, which may lead to potential therapeutic intervention.”

Dr Matthews’ team at Imperial used nuclear magnetic resonance (NMR) spectroscopy to yield detailed insights into the structure of the two nanometre-wide Dr Adhesins.

Their work helps to resolve a long-standing debate amongst microbiologists; it leads to the reclassifying of the Dr Adhesins into a group of bacterial protein appendages known as ’fimbriae’.

These appendages are very difficult to see using the available electron microscopy techniques, and were originally classified as non-fibre or ’afimbrial’.

The new key piece of evidence emerged from some nifty protein engineering of the protein subunit, known as AfaE.

These subunits make up the fibre and cannot fold properly as proteins as they are synthesised with a piece of sequence information missing. In nature, the adjacent subunit possesses this bit of missing information, and ’lends’ it to complete the subunit and build the fibre, in a process known as donor strand complementation.

In the lab, the Imperial team artificially reintroduced the missing protein sequence so that it could complement itself and fold correctly, demonstrating that the fibres assemble in an similar fashion to fimbrial proteins.

The research was principally funded by the Wellcome Trust, and led by the Imperial team with colleagues at the Institut Pasteur, France, the Universities of Edinburgh and Oxford, the University of Texas, Case Western Reserve University, USA, and Adprotech Ltd, UK.

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Tom Miller alfa

More Information:

http://www.imperial.ac.uk

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