Novel toxin receptor discovered for ulcer-causing stomach pathogen

Helicobacter pylori is one tough bug. It can survive in the human stomach, a zone with a pH somewhere between that of lemon juice and battery acid. Now researchers have discovered how an H. pylori toxin gets into cells, a feat that helps the bacterium live in one of the most inhospitable environments in the body.

Their findings appear this week in PLoS Pathogens, a journal of the Public Library of Science.

About half of the world’s population is infected with H. pylori, although most of them don’t know it (most infected people have no obvious symptoms). For a percentage of the infected, however, the bacterium packs a nasty punch. H. pylori is responsible for most human cases of gastric and duodenal ulcers, and long-term infection is a significant risk factor for stomach cancer, the second leading cause of cancer death worldwide.

Researchers have tried for years to understand how the bacterium survives in the human stomach, said Steven Blanke, a University of Illinois professor in the department of microbiology and Institute for Genomic Biology and principal investigator on the study.

“Paradoxically, although H. pylori is a common resident of the human stomach, the bug is not well adapted by itself to acid,” he said. “But this pathogen has several clever mechanisms for carving out a niche for itself in the stomach lining.”

A protein produced by H. pylori, called vacuolating toxin A (VacA), is an important weapon in its arsenal.

“This toxin gets into stomach epithelial cells and immune cells and changes their properties in such a way as to allow H. pylori to first gain a foothold in the stomach, and then survive over the long-term, which may be the entire lifetime of an individual,” Blanke said.

“H. pylori releases the VacA toxin in order to modify its environment,” he said.

How the toxin crossed the membrane to get into these cells was a mystery, however.

Cell membranes are composed primarily of lipids and proteins and are designed to keep things out. Some molecules can penetrate them, but most can do so only after binding to a specific membrane component, called a receptor. Receptors sometimes act as keys that open channels through a membrane, or they function as signaling molecules, communicating to other components in the cell.

Blanke’s team knew that VacA was latching on to something on the cell surface that was helping it across the membrane.

Other studies had shown that VacA bound to lipids within artificially created membranes, so graduate students Vijay Gupta and Hetal Patel screened a number of lipids for VacA binding and soon found one to which the toxin readily attached. This lipid, called sphingomyelin, is an important and abundant component of the membrane of some animal cells. (Foods such as milk, meat, fish and eggs are dietary sources of sphingomyelin.)