Helicobacter pylori the most common bacterial infection worldwide has one less secret in its infective arsenal. Vanderbilt University Medical Centre investigators have identified a receptor that H. pylori uses to bind to the stomach lining and launch its pathogenic attack.
H. pylori infection persists for decades and increases the risk for peptic ulcer disease and gastric cancer. The latest findings, reported recently in the Journal of Biological Chemistry, suggest new therapeutic directions for treating H. pylori infections. The research was selected as a Paper of the Week, a feature of JBC Online that highlights papers which the editorial board members consider to be in the top 1 percent in terms of significance and overall importance. Between 50 and 100 papers are selected each year from more than 6,600 published annually by the journal. New therapies for H. pylori infection clearly need to be developed, said Richard Peek, M.D., chief of Gastroenterology, Hepatology and Nutrition. Current treatment consists of three to four drugs for up to two weeks, a regimen that is associated with poor compliance and only eradicates about 80 percent of treated infections, he said. Understanding the pathogenesis of the bacterium how it causes inflammation in the stomach and how it causes disease will potentially lead to novel therapeutic options. H. pylori bacteria are found everywhere in the world and are especially prevalent in developing countries, where up to 80 percent of adults are infected. In the United States, half of individuals over age 60 are infected. Although not everyone who is infected with H. pylori develops disease, it is the strongest known risk factor for gastric cancer, Peek said. There are certain bacterial factors and host factors that seem to augment gastric cancer risk. We’re interested in both, he said. The spiral-shaped H. pylori bacteria colonise the stomach, living freely in the thick mucus lining. A small proportion of the bacteria about 15 percent actually binds to the epithelial cells of the stomach. It is this binding population that is most relevant for disease, Peek said, because binding induces the secretion of pro-inflammatory molecules and cellular changes that mirror responses to growth factors. Peek and colleagues were interested in determining if a protein called Decay-accelerating Factor (DAF) serves as a receptor for H. pylori. The investigators knew that other pathogens E. coli, coxsackieviruses and echoviruses bind to DAF and that DAF expression is increased in the stomach of patients infected with H. pylori. Only two receptors for H. pylori had been identified, and neither of those fully accounted for observed bacterial binding. Using an in vitro cell system, the investigators showed that human DAF serves as a receptor for H. pylori. They confirmed that strains of H. pylori isolated from clinical samples also bound to DAF, and they defined regions of the protein involved in H. pylori binding. The investigators next examined binding to clinically relevant cells gastric epithelial cell and demonstrated that H. pylori increases the expression of DAF protein. This was consistent with a model in which H. pylori is actually upregulating the expression of its own receptor, Peek said. To translate the findings to an in vivo model, the team infected two types of mice normal mice and mice genetically engineered to lack DAF. H. pylori was able to colonise the two groups of mice to an equal degree, Peek said, but the level of inflammation was markedly different. It was not as if H. pylori couldn’t infect the DAF-deficient mice; it was able to infect the mice, but it was not able to induce inflammation, he said. The studies suggest a model of H. pylori upregulating its own receptor that it then utilises to induce gastric inflammation and injury. Drugs that block the interaction of H. pylori with DAF could be useful in treating infection and preventing disease, Peek noted. New therapeutics are really important for this infection, because it’s so difficult to treat, he added. The studies also open up a whole new bevy of scientific questions, Peek said. How does H. pylori induce expression of DAF? What signaling pathways are activated and how do they ultimately increase the risk for gastric cancer? Which bacterial factors are required for activation of DAF? We’re only at the beginning of this story, he said. (Source: Journal of Biological Chemistry: Vanderbilt University Medical Centre: June 2006).