Judging by the percentage of TV commercials devoted to antacids,stomach discomfort must loom large in the lives of Americans.

When patients complains of gnawing, burning, aching hunger-likepains in the mid-upper abdomen, physicians immediately suspectgastric inflammation or ulcer.

Traditionally, physicians blamed ulcerogenesis on nervous tension _hard-driving, ambitious, executive-type behavior. Other perpetratorsof inflamed or eroded stomach linings include aspirin tablets (theuncoated kind), hot spicy foods and misbehaving hormones. Anddoctors tended to prescribe tranquilizing bed-rest, bland diet, anddrugs that neutralized the gastric acid and enzymes.

Then, a dozen years ago, a couple of Australian scientists unmaskedthe true villain, a spiral-shaped bacterium named Helicobacter pylori.Almost overnight, doctors found that antibiotics could relieve severestomach inflammation and help heal gastric ulcers.

But like a criminal who's caught and jailed but won't talk, H. pyloriremains a molecular mystery to infectious disease researchers.

Three such investigators at Stanford University's Digestive DiseaseCenter shine a thin sliver of light into that black box in today'sProceedings of the National Academy of Sciences (PNAS). They titletheir report: "Helicobacter pylori attachment to gastric cells inducescytoskeletal rearrangements and tyrosine phosphorylation of host cellproteins."

The paper's first author, molecular biologist Ellyn Segal, toldBioWorld Today, "It provides new information on how H. pyloricauses long-term disease, especially relating to gastric cancer."

The malignancy, Segal said, "is usually an either/or proposition. Along-term inflammation will likely develop into either an ulcer or acancer."

Research associate Segal, who runs the infectious disease lab of thepaper's senior author, microbiologist Lucy Tompkins, observed: "Inthe U.S., if you are infected by H. pylori, you have as high a chanceof getting gastric cancer as of getting lung cancer if you are a smoker.In the Third World it's even worse." H. pylori infects perhaps 50percent of the world's population.

Under a thin mucosal sheath, a seamless sac of gastric epithelial cellslines the inner wall of the mammalian stomach. When an H. pyloribacterium hits that wall, it penetrates the mucus membrane, andattaches to an epithelial cell.

"This attachment," Segal said, "produces rearrangement of the cell'scytoskeleton." Specifically, she explained, "it involves creating apedestal," _ a stiff stalk topped by an egg-cup-like receptacle intowhich the bacterium nestles.

But that cytoskeletal rearrangement, she pointed out, "affects otherparts of the cell, possibly involving signal transduction by tyrosinephosphorylation from an extracellular receptor. And thisrearrangement can be regulatory as well as structural.

"Signal transduction," Segal observed, "is hot just now. And tyrosinephosphorylation is usually the start of a molecular cascade, leadingdown possibly to regulating cytokine production. The wholecascade," she said, "is like a leaf that's waving in the air, and all itsroots are down underneath.

"Phosphorylation of gastric epithelial host cell proteins," shecontinued, "is probably going to play a role in the acute inflammatoryresponse to H. pylori infection, leading chronically towardspermanent cellular change."

Can Non-Phosphorylating Mutants Infect?

Since submitting their paper to PNAS last October, Segal and her co-authors have been looking at the correlation between the bacteriallyinduced phosphorylation and the induction of specific cytokines,interleukin-8, IL-6, tumor necrosis factor-alpha, and their pro-inflammatory ilk.

"Coming up next," she said, "I have some genetically generated H.pylori mutants that actually do not induce phosphorylation. We'll putthese into animal models and see what happens, see if they still causedisease. If they don't, that could be very interesting. It could give usan idea of what to look at further."

"The over-arching issue," observed Thomas Monath, vice presidentof research and development at OraVax Inc., "is, if one couldunderstand what bacterial factor leads to attachment, one couldclearly develop strategies that might help clear this infection. Oneobvious way is to develop vaccines directed against, or composed of,the attachment molecules on the surface of the bacteria. Antibodies orimmunity against those could prevent this phenomenon."

This is what OraVax, in Cambridge, Mass., is undertaking, jointlywith Paris-based Pasteur Merieux Serums and Vaccins S.A. (SeeBioWorld Today, April 13, 1995, p. 4.) n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.