Only one microorganism on earth can possibly colonize the corrosive, high-acid environment of the human stomach. This is the now-infamous pathogenic bacterium, Helicobacter pylori.

One of its two discoverers some 20 years ago was an Australian hospital resident named Barry Marshall. His claim to fame included gulping down a flask containing 1 billion copies of H. pylori. He woke up hungry and irritable, with a headache, halitosis and gastritis - inflammation of the stomach. Two weeks later, all those symptoms were gone. But H. pylori has been very much with the human condition ever since. (See BioWorld Today, July 31, 2002.)

Updating its sinister story is an article in Nature Genetics, released online Feb. 24, 2003, and titled: "Mice deficient in protein tyrosine phosphatase receptor type Z [Ptprz] are resistant to gastric ulcer induction by VacA of Helicobacter pylori." Its co-authors are researchers at several universities in Japan.

Capping their report is a "News & Views" commentary authored by gastroenterologist Richard Peek Jr., at the Vanderbilt School of Medicine in Nashville, Tenn. It's headed: "Intoxicated cells and stomach ulcers."

"The overall finding or message of that Japanese paper," Peek told BioWorld Today, "is that its authors have identified a novel pathway through which a disease-associated H. pylori constituent can bind to a host receptor, induce cellular detachment in vitro, and hemorrhagic gastric ulceration in vivo. This is the first mechanism through which an ulcer-associated protein of H. pylori may actually lead to gastric mucosal damage and ulceration.

"If you add this VacA protein to gastric epithelial cells in vitro," Peek continued, "what you often see is the formation of vacuoles. And that's how VacA got its acronymic name - the vacuolating cytotoxin. Now these investigators punch multiple holes in the cells' endosomes, making them look like microscopic Swiss cheese. A vacuole typically makes 5 percent or 10 percent of the cell volume.

"The bacterium persists in the stomach for the lifetime of its human host," Peek pointed out. "It's an unusual infection in that generally it has no other bacterial competitors in the stomach. All that time it is inducing gastric inflammation. About 10 percent of the bacterial population adheres to gastric epithelial cells, while the remainder stay within the gastric mucus gel layer. As far as any beneficial effect on the bug, no one really knows."

How Does H. pylori Acid-Proof Itself In Stomach?

"Several protective mechanisms permit H. pylori to survive in the hostile environment of the stomach acids," Peek noted, ticking them off: "One, it has flagella - hairlike paddles - that allow it to be freely motile within the gastric mucus gel layer. That helps them resist stomach contractions or peristalsis. Two, H. pylori produces an enzyme called urease, which helps it to buffer the harsh acidity of the stomach. Three, it is able to induce gastric inflammation, which can potentially provide uptake of nutrients, such as iron or nickel, for the bacteria to survive. And a recent report indicated that H. pylori produces another enzyme, argenase, that prevents it from attack by its host's nitric oxide [NO]. NO is a bactericidal molecule."

H. pylori has a weirdly complex inheritance pattern. "As far as the bacterium goes," Peek explained, "there's a high level of genetic diversity, which can consist of the presence or absence of genes, altered by point mutations - another type of diversity. They're genes that have different alleles - polymorphisms. VacA is one of those genes. Its insertions and deletions occur throughout the genome. And one can compare the two bacterial strains that have been completely sequenced. About 7 percent of their genes are strain-specific - making for a highly adaptable bacterial population.

"We had an article in PNAS," Peek recounted, "which looked at the genetic diversity evolution in one patient, which recurred every six years. It was tremendous in that every isolate that we tested from this single patient, using DNA chip arrays, was genetically unique.

"As for H. pylori's human host," he went on, "the transmission is uncertain because it's a chronic infection. Usually by the time we find out that somebody's infected, it's years after the infection events have occurred. What we do know is that most infections appear in childhood, and that mother-to-infant transmission is a very strong risk factor. Patients who have polymorphisms or alleles that allow high expression levels of those inflammatory molecules seem to be at higher risk of getting disease. Only 10 [percent] or 15 percent of patients who are infected with HP will ever get ulcers or gastric cancer.

"We think that the risk for disease in infected patients depends on very specific and choreographed interactions between bacterial virulence constituents in host proteins," Peek observed. "The epitome of this is the Japanese paper.

"H. pylori is one of the most common bacterial infections worldwide, but in developed countries, such as the U.S. and Western Europe, the incidence of HP infection has been decreasing in the last century - dropping every decade. The postulate is that it's due to heightened increase in sanitation conditions. The situation is diametrically different in developing countries. Over 90 percent of children by the age of 12 are likely to be infected."

In Vivo Mice Validate Receptor Rationale

"The first thing the Japanese authors did in vivo," Peek recounted, "was look for the presence of this Ptprz receptor in wild-type mice, and knock out its gene from other animal cohorts. They saw that it was expressed on gastric epithelial cells and not in their KO mice. They then added VacA to both murine populations, wild type and KO, and found that VacA got into the cells in all of the mice, suggesting that there are multiple receptors for VacA on the epithelial cells. But they only saw bleeding ulcers in gastric mucosa in the mice that had this receptor.

"Based on these results," Peek summed up, "one can examine the possibilities for human therapy, diagnostics or vaccines. Now we can design a compound that would block the interaction of VacA with the Ptprz receptor antagonists yet to be developed, and maybe prevent the induction of ulcers. Vaccinating patients with VacA could potentially induce a humoral or antibody response that would block this cytotoxin. The authors in Japan," Peek concluded, "are working in that direction."