Understanding and exploiting regulation in pathogenic enteroaggregative Escherichia coli

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Many bacteria cause diarrhoea in humans because, when they are ingested, they colonise the lower gut by attaching to the lining of the intestine. They then produce products that cause abnormal levels of fluid build-up in the host's gut. For most people, such diarrhoea is merely an irritation, but, for some, it can be life-threatening. Currently, one especially troublesome cause of diarrhoea, in both developed and developing countries, is enteroaggregative Escherichia coli (EAEC). This harmful organism probably evolved from harmless Escherichia coli strains following the acquisition of a score or so of extra genes that allow it to attach to human intestines and cause diarrhoea. Studies with EAEC and with other harmful bacteria have shown that the expression of these extra genes, which cause disease, is tightly controlled. For EAEC, and related harmful bacteria, we now know what the principal regulators are. Interestingly, the most important of these regulators was acquired with the other extra genes, and its role appears to be mainly to make sure that the harmful bacteria only express the disease-causing genes when the harmful bacteria are in the host. Hence the main aims of the work proposed here are to do experiments that will tell us how the main regulator is activated when the bacteria get to the gut, and how the activity of the regulator is turned on and turned off. We plan to look at EAEC strains from patients from different countries to see if the same mechanism is always used and also to check the harmful genes in the different strains. Once we have understood how the regulator works, we will use genetic engineering techniques to make derivatives of the regulator that are defective and so will interfere with virulent strains. We will devise ways to deliver the defective regulator to harmful cells during infection with a view to developing a new way to treat bactreial infection that involves 'disarming' the harmful bacteria rather than killing them.