Helicobacter pylori and peptic ulcer disease
Helicobacter pylori, a human specific gastric pathogen, first isolated in 1982 (Lancet, 1273, 1983) has emerged as the causative agent in chronic active gastritis and peptic ulcer disease (Emerging Infectious Diseases 1, 79 1995). In developing countries, the majority of the population is infected already in early childhood, whereas in the industrialized world, less than 20 % of young people are infected, increasing to about half the population by 50 years of age. However, infection prevalence is still very significant because of the medical impact of H. pylori-associated disease. About 10% of people in Sweden develop peptic ulcer sometime during the lifetime. Once an established infection, the bacteria can persist for the lifetime of the host. Interestingly, most infected individuals show no clinical symptoms, implying the influence of additional factors in the pathogenesis of the disease such as the infecting strain. The chronic infection has been correlated to the development of gastric cancer, one of the most common forms of cancer in humans and H. pylori was recently defined a class 1 carcinogen (Lancet, 344, 1078 1994). H. pylori colonizes the human gastric mucosa by adherence to the stomach lining. These adherence properties protect the bacteria from the extreme acidity of the gastric lumen and displacement from the stomach by forces such as gastric emptying. Central to current thinking in pathogenesis is the importance of adherence for colonization and disease.
Fig1. Histo section of H. pylori infected human stomach cells. Bacteria (the orange stained small dots in the center) are seen directly adhering to the surface mucous epithelial cells.
The bacterial binding sites (receptors) in the stomach
Bacteria express adhesion molecules that recognize specific carbohydrates on the stomach cell surface. We have demonstrated the fucosylated blood group antigen Lewis b and H to mediate adherence of H. pylori to human gastric epithelial cells in situ (T. Borén et al. Science 262, 1892 1993). The fucosylated blood group antigens H-1 and Le b are typically found on erythrocytes where they define the O phenotype in the ABO blood group system, but they are also expressed on the epithelial cell surfaces in the stomach.
Blood groups and peptic ulcer disease
A relationship between blood group phenotype and the development of duodenal ulcer disease has received attention ever since the discovery by Aird et al.(1954) “An association between the ABO groups and peptic ulceration” Br Med J ii, 315-321, that individuals of blood group O phenotype run an approximate 1.5-2 fold increase in developing acid peptic disease The epidemiological data indicates the possibility that individuals of blood group O phenotype might have higher levels of H. pylori (histo-blood group antigen) receptors available in the gastric epithelial lining, mediating attachment of the H. pylori bacteria and promotion of the microbial colonization process/ development of disease.
Fig.2. Cell-specific adhesion of green-labeled H. pylori bacteria to the human gastric (stomach) mucosa, analyzed by the in situ adherence assay (T. Borén et al. Science 262, 1892 1993).
The potential of the BabA adhesin protein as a vaccine candidate
We have also identified the corresponding histo blood group antigen binding H. pylori adhesin, the BabA adhesin, by a novel technique developed for the purification of the adhesin protein; Receptor Activity Directed Affinity Tagging, i.e., ReTagging (D. Ilver/T. Borén et al. Science 279, 373, 1998).
The clinical relevance of the BabA adhesin was recently demonstrated. The virulent H. pylori strains, expressing CagA-protein, the Vacuolating Cytotoxin, and the BabA-adhesin ("triple-positive strains") were found to be highly associated with peptic ulcer disease and gastric cancer. The triple-positive strains were significantly less associated with gastritis compared to the CagA and VacA positive type I strains (Gerhard M et al. Clinical relevance of the Helicobacter pylori gene for blood-group antigen-binding adhesin. Proc Natl Acad Sci USA.; 96:12778-12783, 1999).
The NIH (US), and Läkemedelsverket (Sweden) recommend antibiotic treatments against peptic ulcer disease but antibiotic resistant strains of H. pylori are already prevalent. A vaccine strategy based on the present findings about the BabA adhesin could subsequently be used to target against the virulent type I H. pylori strains, Such an approach could be of additional importance if the recent suggestion that less virulent strains could be regarded as members of the commensal (normal) bacterial flora, proved to be correct (Lancet, 349, 1020, 1997).
We propose that BabA-mediated H. pylori adherence to gastric epithelial tissue plays a critical role in efficient delivery of H. pylori virulence factors that damage host tissue directly, incite inflammatory responses and, in addition, provoke auto-immune reactions, that cumulatively lead to development of ulcer disease. The presence of biologically conserved motifs and peptide sequences provides a unique target for vaccine based antimicrobial strategies. As a consequence of the high receptor specificity in the adherence process and the requirement of biologically conserved receptor binding adhesive motifs i.e., specific adhesin proteins, the microbes might have been forced to accept the potential Achilles heel of adhesin proteins as vaccine candidates. In this respect, the BabA adhesin will be a prime candidate for the development of a functional and cost-efficient vaccine.
Immunization experiments with adhesin proteins of uropathogenic E. coli demonstrate the potential in the generation of an immune response based on antibodies with adhesion inhibitory properties (Science, 276, 607 1997, i.e. the immune response will have the dual/ synergistic effect of both providing complement activating antibodies and, in addition, antibodies that will bind directly to the receptor binding domain of the adhesin protein and subsequently prevent the bacterial adherence and colonization process.
Vaccination could either be regular immunization by use of needle or could be by administering the protein antigen directly, e.g. given as an oral drinking solution, i.e., similar to the drinkable cholera vaccine (SBL-Vaccin). |
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Research & Development 
