With the recognition that gastric infection was associated with ulcer disease also came the realization that infection was five times more frequent than ulcers. Much effort has been expended in attempts to identify the culprit genes responsible for the pathogenic consequences of infection. This is probably going to be extended to identifying genes also responsible for carcinogenesis.

Pathogenicity is either due to the organism itself being able to enter cells in the stomach or is the result of proteins released by lysis or secretion from the organism and then taken up by the cells or being injected into the cells of the gastric epithelium. There is no evidence that the first process takes place; hence, the lytic, secretory, or injected products of H. pylori must play the central role in the response of the surface epithelium of the upper gastrointestinal tract to infection.

However, although symptomatic disease is an infrequent outcome of infection, gastritis is a universal response. The inevitable gastritis that results from infection may well relate to the generation of NH₃ by bacterial urease. The finding that the vast majority of urease activity results from acid activation of internal urease promotes the idea of synergism between the organism and acid in causing initial damage. An increase of NH₃ on the surface of gastric cells results in an increase of intracellular pH. In turn, this results in an increase of intracellular calcium and initiation of calcium signal-dependent phenomena. These could be the harbingers of arrival of inflammatory cells that, in turn, produce the cytotoxic effects observed.

For H. pylori to establish and cause gastritis, it is likely that specific adhesion must occur to the surface membrane of gastric cells. The organisms tend to bind at regions of contact between cells in vivo and in vitro. These regions may contain specific receptor proteins for the organism, such as cadherins, integrins, or Lewis-type antigens. Such points of contact can result in pedicle formation and changes in intracellular distribution of cytoskeletal elements, perhaps aiding initiation of cell pathology.

The first unique protein identified as increasing host response was CagA, a protein of approximately 120 to 140 kDa. Its function is unknown, but it is part of what has been called a pathogenicity island. As for other bacteria, this region, which contains approximately 40 genes, appears to affect virulence. This island in H. pylori and other organisms contains DNA with a different base composition compared to the rest of the genome and is thought to have been acquired by horizontal transfer from another organism. Another product that is coexpressed with CagA is VacA. There are several variants in this region, showing that this gene is a mosaic. Another gene more recently identified with virulence is iceA. There appears to be a relatively clear relationship between expression of those genes and clinical outcome.

Within the pathogenicity island, there are a number of membrane-inserted proteins, many thought to be involved in export of proteins. The most frequently used protein-secretory pathway is that involving the secretory mechanisms, which relates to cotranslational insertion of a cleavable signal sequence into the translocon. After insertion of this sequence, the rest of the protein is
externalized, and the signal sequence is cleaved outside the inner membrane, resulting in export of the protein.

For externalization of the flagella, a different system is used—the type III secretory system. The flagellar motor proteins are part of this, and a specialized protein is also present in the outer membrane that allows extrusion of the flagellar protein in proper orientation through both membranes. That type IV secretion exists in the organism, with direct injection of bacterial protein into host cells, has also been suggested.

Protein secretion by H. pylori

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