Scientists discover new intricacies in how ulcer bugs stick to stomach

July 22, 2004

St. Louis, July 22, 2004 -- Scientists working to develop a vaccine for the bacterium Helicobacter pylori, the primary cause of ulcers and a contributor to stomach cancers, have uncovered new intricacies in the way the bacterium sticks to the lining of the human stomach.

A multinational team of researchers showed that babA, a protein that helps H. pylori stay in the stomach, has evolved in many strains of the bacteria in Latin America. The protein is used by virulent strains of H. pylori that are the targets of a long-term vaccine development effort.

"If we can improve our understanding of how H. pylori adheres to the stomach lining, we may be able to develop better ways to prevent or decrease infections," says Douglas E. Berg, Ph.D., Alumni Professor of Molecular Microbiology at Washington University School of Medicine in St. Louis and a contributor to the research, which appears in the July 23 issue of Science. "H. pylori is a very clever pathogen, but its need to stick to the stomach lining may be its Achilles' heel."

Epidemiologists estimate that H. pylori infections are present in over half of the world's population. Most infections in the United States and other industrialized nations can be treated with antibiotics, but treatments are too costly for many sufferers in underdeveloped nations, where the bacteria's pervasiveness and poor sanitation significantly increase the risk of repeat infections. In addition, resistance to standard drug therapies is a major problem in these countries.

H. pylori can survive in human stomachs for decades, employing many tricks to do so. To avoid being flushed out by digestive processes, the bacteria stick to cells lining the stomach wall, from which they also steal nutrients.

BabA, one of several "adhesins" that help H. pylori stick to the stomach wall, binds to a carbohydrate structure known as the Lewis b antigen receptor. In humans with different blood types, this receptor either stands alone (blood type O) or contains additional sugars (blood types A and B), changing the shape of the target babA seeks to bind.

"Most human populations have a mixture of people with blood types A, B and O. When the bacteria spread from one person to another, they can't predict the next host's blood type, so they maintain a form of babA flexible enough to bind to all the different Lewis b receptors," explains Berg, who is also a professor of genetics and of medicine. "In Amerindian populations in Latin America, though, almost everyone has blood type O."

When Berg and colleagues took a detailed look at 59 different H. pylori strains in impoverished neighborhoods around Lima, Peru, they found that 60 percent had a form of babA that had lost its flexibility--it no longer could bind to anything but the version of Lewis b associated with blood type O.

"You might call these strains the specialists, and other versions of H. pylori the generalists," Berg says. "These specialist strains are related to Spanish strains of H. pylori, so these adaptations must have occurred since Spanish conquistadors arrived, introducing their bacterial strains to the peoples of the New World."

Surprisingly, specialist babA doesn't bind to Lewis b any tighter than generalist babA. This suggests the specialist type may have developed not because of an advantage for the bacteria but through simple attrition of the generalist form.

"We suspect that the bacteria have a tendency over the course of multiple generations to genetically deactivate and reactivate babA proteins that allow them to stick to the stomach lining, and that during these cycles the ability to bind to other forms of Lewis b may have been lost," Berg explains.

The ability to turn these proteins off insures that some bacteria can more easily break away from the stomach lining.

"Some people's immune systems mount a strong inflammatory response to H. pylori that can actually wipe out the bacteria, so from the bacteria's 'perspective,' it's always good to have some bacteria that can break loose and escape," Berg explains.

Berg and collaborators are working to understand the details and causes of this cycle and the activities of the proteins involved.

"We're hoping that through combined approaches to blocking adhesion we may be able to prevent infection," Berg says. "It's possible, though, that we may have to set our sights on decreasing the severity of infections, which will limit the damage to the stomach and reduce cases of stomach cancer and ulcers."

The lead investigator for the study was Thomas Borén, Ph.D., D.D.S., professor of medicinal biochemistry and biophysics at the University of Umeå in Umeå, Sweden. Borén was a postdoctoral student at Washington University School of Medicine 10 years ago.

"This is the third important paper on adhesins in babA that we've produced," Berg says. "Washington University and the University of Umeå have an exchange program that helps us keep this fruitful collaboration going strong." Researchers from Peru, Spain, Puerto Rico, Germany and Japan also were involved in the study.
Aspholm-Hurtig M, Dailide G, Lahmann M, Kalia A, Ilver D, Roche N, Vikström S, Sjöström R, Lindén S, Backström A, Lundberg C, Arnqvist A, Mahdavi J, Nilsson UJ, Velapatiño B, Gilman RH, Gerhard M, Alarcon T, López-Brea M, Nakazawa T, Fox JG, Correa P, Dominguez-Bello MG, Perez-Perez GI, Blaser MJ, Normark S, Carlstedt I, Oscarson S, Teneberg S, Berg DE, Borén T. Functional adaptation of babA, the H. pylori ABO blood group antigen binding adhesin. Science, July 23, 2004.

Funding from the Mizutani Foundation, The J.C. Kempe and Seth M. Kempe Foundation, the Umeå University-Washington University Exchange Program, the Commission of the European Union, the Swedish Medical Research Council, the Swedish Cancer Society, the Swedish Foundation for Strategic Research (SSF), the Umeå University Biotechnology Fund, the County Council of Västerbotten, the Royal Swedish Academy of Sciences, the Swedish Medical Society, the Swedish Society for Medical Research, the J.C. Kempe Memorial Foundation, Washington University, and the National Institutes of Health.

Washington University School of Medicine

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