Immunosuppressive and Proinflammatory Activities of the VacA Toxin of Helicobacter pylori

20 yr have elapsed since the discovery of the association of the then novel bacterium Helicobacter pylori with different gastroduodenal diseases, including severe active chronic gastritis, gastroduodenal ulcers, adenocarcinoma, and lym-phoma (1). The amount of research performed from the clinical to the molecular level is impressive (2). It is presently well established that H. pylori infects the large majority of the human population with a very high prevalence in countries with poor hygienic conditions. H. pylori is human specific and resides in a defined ecological niche comprising the stomach mucus layer and the stomach epithelial lining. The infection is chronic and life lasting if not treated with antibiotics. Only a minority of the infected persons develop gastroduodenal diseases, suggesting that an adverse outcome of the infection depends strongly on the response of the host and/or on the interplay with the genetic background and other factors. As a result, our present knowledge of the molecular and cellular steps of the pathogenesis of the H. pylori –associated diseases is very limited. An additional difficulty is that in vitro experiments must be performed within short time windows of hours to weeks, whereas in vivo the disease develops over years to several decades. Moreover, the pathogenesis in animal models of infection differs substantially with the human disease. The VacA Toxin. It is conceivable that a bacterium causing a life-lasting infection has evolved to produce many factors that permit colonization and prolonged persistence in the unique environment of the stomach. Several virulence factors of H. pylori have been identified, and their mechanisms of action at the cellular and tissue level are being actively investigated. One factor that has attracted major attention is the vacuolating cytotoxin (abbreviated VacA), which was first identified as a protein present in H. pylori supernatants that was capable of inducing the formation of membrane-bound vacuoles in cells in culture (3, 4). This toxin is made in the bacterial cytosol as a four-part protein consisting of (a) an inner membrane secretion signal sequence of variable nature, which is responsible for the fact that different H. pylori strains secrete different amounts of VacA; (b) a 37-kD domain (p37) essential for the vacuolating activity; (c) a 58-kD domain (p58) essential for receptor binding; and (c) an autotransporter domain, which drives VacA (p37-p58) across the bacterial outer membrane and is then removed by specific proteolytic cleavage. VacA may remain associated with the bacterial surface or …