For most non-scientists the term E. coli conjures up images of undercooked hamburgers and diarrhoea. However, ask a general biologist and the image of E. coli could not be more different.

The E. coli bacterium is used in laboratories the world over as an invaluable tool to study all sorts of genes and produce almost any chosen protein. E. coli is ideal for this role because its biology is relatively simple, it grows very quickly, it is easy to keep and is nearly always harmless. Despite its infamous public image, E. coli is generally a ‘good’ bacterium found within our digestive tract where it causes no problems at all and may even be beneficial. The problem arises when this amiable little bug picks up bad pieces of DNA from the environment, turning it from a passive, commensal bug into a potentially serious killer. Just a few simple transactions of DNA, combined with a several million years of evolution, and E. coli has become a feared infectious agent, capable of killing over a million people each year, particularly young infants or people with compromised immune systems.

So what makes E. coli so deadly? A virulent form of E. coli (also known as EPEC) has recently had almost every one of its genes identified by the Sanger Institute in Cambridge, giving us a massive advantage in searching for the genes that cause disease. In Bristol the lab is particularly interested in how E. coli is able to cause food poisoning and diarrhoea. Over the past few years research has shown that at some point in its evolution E. coli acquired a piece of DNA that gave it the ability to physically ‘inject’ proteins and toxins into the cells of our digestive tract. It actually possesses a molecular ‘syringe’ to transfer more than 20 different proteins into the cells of our gut. Once inside the cell, the proteins do a huge variety of things and manipulate the cell for the needs of the bacterium – and in the process our cells get sick and cannot function normally – the result is diarrhoea. What advantage this gives to the bacteria remains unclear. The importance of the piece of acquired DNA can be demonstrated in the lab by putting it into harmless E. coli, which then gives it the ability to inject proteins into our cells.

So what makes E. coli so deadly?

  What our work has shown recently is that many of the proteins injected by E. coli interfere with the way human cells contact one another. Under normal conditions, cells in the intestine are very tightly joined to each other by closed ‘junctions’. These create a barrier to the passage of water and stop it leaking out from the body into the gut. By opening the junctions, the E. coli proteins disrupt this cell-made barrier, allowing water to pass through them, which contributes to what we know as diarrhoea. Even more interesting is the fact that the bacteria neatly controls the activity of the injected proteins, only allowing them to act at set times after injection. This activity is directed by yet another bacterial protein on the surface of E. coli that never even enters the intestine cell. So, from its ringside seat on the surface of the intestine cell, E. coli appears to be telling its protein what needs to be done – and the outcome is diarrhoea.

The potential advantages to be derived from this research are massive

There is an astonishing amount of similarity between the injected proteins of E. coli and other bacteria that cause disease including Salmonella, Shigella and Yersinia (which was responsible for the plague). So, by understanding how the normally harmless E. coli has acquired the ability to cause disease we gain a huge amount of insight into how bacteria in general cause disease and, maybe more importantly, it also provides us with knowledge about how our own cells work. For example, little is known about the mechanisms behind how the cellular ‘junctions’ are controlled in our intestine, ie what keeps them tight shut. Our work has identified five bacterial proteins that are important in facilitating E. coli to open the junctions, allowing a clearer dissection of some of the mechanisms by which these essential junctions work. In terms of therapeutic potential, the advantages are obvious. By understanding how E. coli is able to open up the junctions to cause diarrhoea, we may be in a position to close them back up again, possibly halting disease. In addition, all the other E. coli proteins that are injected into the cell also have many other functions and the same principle applies to each one. By knowing which proteins are the most important in disease, we now have potential targets for use in immunisation programmes, particularly for vulnerable people in infected areas.

So, from a simple, normally harmless bacterium that exists by the millions in each and every human gut, we are able to learn a huge amount about how bacteria cause disease and also how our own cells function. Until recently only five injected EPEC proteins were known, but this year alone, over 20 injected proteins have now been identified. Clearly, we have only reached the tip of the iceberg in discovering how the injected proteins subvert our own cells, but the potential advantages to be derived from this research are massive.

Dr Paul Dean moved to  the Institute for Cell and Molecular Biosciences, University of Newcastle upon Tyne in 2004. This work was supported by the Wellcome Trust.