The rod-shaped bacterium Helicobacter pylori colonizes the surface of the cells that make up the lining of the stomach, and can cause gastritis, peptic ulcers and gastric cancer. The bacterium attaches firmly to the apical surface of the gastric epithelium by binding to specific receptor structures on its target cells, and is capable of replicating there. Researchers led by Professor Rainer Haas at LMU’s Max von Pettenkofer Institute have now identified a novel class of receptors for the pathogen, and show that these are intimately linked to the pathogenic processes initiated by the microorganism in the gastric epithelium. The new findings appear in the journal Nature Microbiology.
Chronic infection of the gastric epithelium has been identified as a major risk factor for the development of stomach cancer. To gain a better understanding of the mechanisms that underlie the disease process, Haas and his team set out to identify the receptors involved in the initial binding of the bacterium to its target cells. “We found that receptors of the so-called CEACAM family on the surface of the epithelial cells play an important role in binding,” he says. “Unlike all previously known receptors for Helicobacter, CEACAM binding does not require sugar/carbohydrate molecules, and therefore represent a hitherto unknown class of receptors for H. pylori.” The team also identified the interacting partner for CEACAMs on the bacterial surface the protein HopQ, thus demonstrating that the latter serves as a so-called adhesin.
Moreover, Haas and colleagues discovered that the HopQ-CEACAM interaction is not only important for recognition and binding of the bacterium by its target cells. It also plays a crucial role in pathogenicity, which is mediated by the translocation of bacterial virulence factors into the cell. The major virulence factor responsible for pathology is the protein CagA. In highly pathogenic strains of H. pylori, delivery of CagA is carried out by a specialized protein complex, which acts similar to a syringe. Crucially, as the new study shows, the action of this sophisticated secretion system is directly triggered by the binding of HopQ to CEACAMs. Haas and colleagues assume that binding of H. pylori to CEACAMs activates a signal relay, which ultimately induces a functional change in the host cells that enables the bacterium to inject CagA. Haas now plans to elucidate the nature of the signal and its impact on the epithelial cells – with a perspective to blocking the reaction for therapeutic purposes. As he points out, “specific inhibitors of the HopQ-CEACAM interaction should either block infection completely or prevent the injection of CagA.”
The findings made by the Haas team have been independently confirmed in a study done by groups led by Prof. Markus Gerhard of the Technical University of Munich (TUM) and PD Dr. Bernhard B. Singer at the Duisburg-Essen University, which also appears in the new issue of Nature Microbiology. The research was supported by the German Research Foundation (DFG) and the German Center for Infection Research (DZIF).