Helicobacter pylori is a Gram-negative spiral-shaped bacteria that resides in the gastric mucosa and adheres to the epithelial lining of the human stomach. H. pylori adhesion mediates inflammation of the epithelium, which can lead to more severe diseases such as chronic active gastritis and gastric carcinoma. In order to adhere tightly to the mucosal lining, H. pylori expresses adhesion proteins called adhesins. The best-charachterized adhesins are blood group antigen binding adhesin, BabA, and sialic acid binding adhesin, SabA. During chronic infection there is an adhesion/inflammation-associated balance between BabA- and SabA-mediated binding modes. BabA is the major mediator of binding when the stomach is in good health and the corresponding binding receptors are ABO blood group antigens such as the difucosylated Lewis b antigen that is expressed on MUC5AC mucins by the surface epithelium. However, in chronic inflammation of the gastric mucosa there are dynamic shifts in the glycosylation patterns; in inflamed gastric tissue, SabA is an important mediator of bacterial binding and adherence. The corresponding binding receptors for the SabA adhesin are complex sialylated antigens such as sLewis x (sLex) and sLewis a (sLea). In this thesis, I describe our findings that SabA also promotes H. pylori binding to red blood cells in the gastric mucosal small blood vessels. The minimal binding epitope on the erythrocyte surfaces is the sialylated NeuAcα2-3Gal-disaccharide and this bacterial adherence promotes hemagglutination, i.e. the rapid aggregation of the erythrocytes.
Another important finding is that the binding properties of SabA are of polymorphic nature. In particular, clinical isolates demonstrate variant types of relative binding affinity for the series of sialyl-di Lewis x (sdiLex), sialyl-Lewis a (sLea) and sialyl-lactosamine (sLn). The relative binding to sialylated glycans is strain dependent and H. pylori strains J99 and SMI9 display different SabA-mediated binding modes for sialylated glycans. By introduction of the sabA gene from strain J99 into strain SMI9, the detailed binding mode of SMI9sabAJ99 was altered and preferably displayed the original binding mode of strain J99. Thus, the polymorphism of SabA-mediated binding is an inherent property of the adhesion protein itself, i.e. the polypeptide itself and is not encoded or influenced by the strain genome background. The individualized binding properties or polymorphism in binding modes provides SabA with the opportunity to adapt to individual hosts and to the inflammatory changes in glycosylation. SabA expression makes use of slipped-strand mispairing for H. pylori to swiftly attach and detach from the epithelium. Furthermore, the ability to fluently attach and detach from the epithelial surfaces is an important feature of H. pylori and its ability to evade the mucosal inflammatory responses, as well as from the rapid turnover and shedding of gastric mucosa. Here, I describe a novel blood group antigen binding outer membrane protein, FecA3. This is an adhesin candidate, which independently of BabA, binds the series of fucosylated blood group antigens. The similar binding modes of BabA and FecA3 for ABO blood group antigens is not fully understood but the expression of FecA3 is regulated by the nickel-responsive regulator NikR, which acts as a sensor regulated by the availability of free nickel ions. Ni2+increases when pH is lowered, thus regulation of FecA3 is suggested to be governed by local pH. Taken together, the high-affinity binding by BabA, and continuous biopanning for the fittest, in particular for the low-affinity binding of FecA3, might be contrasting but complementary properties and features of the different adhesins that are of importance during different stages of mucosal inflammation and disease development.