LONDON - Most pathogenic bacteria get what they want in life - food, and a comfortable place in which to replicate - with the help of strategies for evading their hosts' immune systems.

Now comes the first example of a bacterium that switches on the immune system in order to provide it with more cells it can infect.

Researchers in the U.K. established that entero-pathogenic Escherichia coli (EPEC), a major pathogen of children in both the developed and developing world, uses the intimin protein present on its surface to stimulate T cells present in the gut wall. T-cell activation in the gut wall then causes increased growth of the gut epithelium, boosting the amount of mucosa available for the bacteria to colonize.

Thomas MacDonald, professor of immunology at St. Bartholomew's and the Royal London School of Medicine and Dentistry in London, told BioWorld International: "If we could make a vaccine against intimin, we would be able to prevent infant diarrhea. In addition, because intimin can drive mucosal T-cell responses, it can be used to boost mucosal immune responses to other potential vaccines, such as those to protect against Salmonella and typhoid fever, for example."

Commenting on the study, John Walker-Smith, professor of pediatric gastroenterology at Royal Free and University College Medical School in London, said: "This discovery is important because it means we now have a clear hypothesis to account for the disease process which follows EPEC infections, and may persist when the child becomes sensitized to a dietary antigen such as cow's milk protein. It means we may be able to intervene to prevent this unfortunate chain of events, which is a potent cause of persistent diarrhea and malnutrition, a major problem for infants, particularly in the developing world."

MacDonald and his colleagues reported their results in a paper in the July 23, 1999, Science, titled: "Role of Bacterial Intimin in Colonic Hyperplasia and Inflammation."

Gad Frankel and Gordon Dougan, of the Department of Biochemistry at Imperial College of Science, Technology and Medicine in London, both co-authors of the paper, have studied intimin and hold a patent on it. During their studies into how the bacteria use intimin to bind to epithelial cells, the finding that intimin is a potent activator of T cells came as a surprise - although recent structural studies have shown that intimin has regions capable of interacting with T cells.

These two researchers now are working on how to include intimin in vaccines in order to boost mucosal immune responses. The team is interested in hearing from potential partners to help them develop the work further.

MacDonald's interest in intimin developed after he found out the protein was involved both in EPEC, and in murine infection with Citrobacter rodentium. The latter is a mouse model for human EPEC infection. It also results in changes to the gut mucosa that are indistinguishable from murine inflammatory bowel disease: the gut mucosa thickens and the surface of the epithelium increases.

MacDonald and his team found that intimin was "the most amazing T-cell stimulant we have ever seen." They then embarked on some experiments with mice to find out whether it was the host immune response to infection with C. rodentium that was causing these changes, or the intimin itself.

They took various strains of bacteria, which expressed either the type of intimin found in C. rodentium, in EPEC, or neither, or a mutated type of intimin that cannot bind to T cells. They killed the bacteria with formalin, before delivering them to the colons of mice. They found the mice that received killed bacteria, which had intimin on their surface, developed signs of inflammatory bowel disease, indistinguishable from live infection, while the colons of those receiving mutated intimin (or none at all) remained normal.

In a further experiment, they put normal C. rodentium into the colons of mice that had been genetically modified so that they did not have receptors for gamma interferon, and therefore had depressed cellular immunity. Those mice also failed to develop signs of inflammatory bowel disease.

"These experiments show," MacDonald said, "that it's not the host response to infection that is causing this pathology, but the bacterial intimin. It makes a lot of sense that the bacteria can do this, because they are driving the immune system for their own advantage. We have previously established that T-cell responses in the gut wall invariably result in increased epithelial proliferation and the bacterium takes advantage of this host response."

Future work will address which cells in the gut intimin interacts with, and whether the protein has activity in human beings. "We want to see if it boosts T-cell responses in cells isolated from human gut, and in model systems of the human gut disease, to see if intimin can drive inflammation," MacDonald said.

The group also is examining a theory that the immune response stimulated by EPEC may trigger conditions such as coeliac disease and cow's-milk intolerance in children.

MacDonald said, "The bacterium has no way of selecting which immune responses it elicits. We think that when children get infections with EPEC, the intimin may drive T-cell immune responses to whatever is around in the gut at the time - whatever the child happens to have been eating. This could go a long way toward explaining why some individuals make T-cell responses to wheat in coeliac disease. It could be a key environmental event which breaks the tolerance that most of have to the things we eat."