Scientists Discover Novel Toxin Receptor for Ulcer-causing Stomach Pathogen

by VR Sreeraman on  May 25, 2008 at 10:51 AM Research News
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 Scientists Discover Novel Toxin Receptor for Ulcer-causing Stomach Pathogen
A research team, including two Indian-origin scientists, has discovered that ulcer-causing stomach pathogen, called Helicobacter pylori, enters the stomach's inhospitable environment via a novel toxin receptor called sphingomyelin.

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.

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

Human stomach is a zone with a pH somewhere between that of lemon juice and battery acid.

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

He said that 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. H. pylori releases the VacA toxin in order to modify its environment," Blanke said.

However, the researchers did not know how the toxin crossed the membrane to get into these cells. Usually cell membranes made of lipids and proteins can be penetrated by molecules that can bind to specific membrane component, called a receptor.

The researchers knew that VacA was binding on to some receptor on the cell surface that was helping it across the membrane. It was indicated through previous studies that VacA bound to lipids within artificially created membranes.

This led Vijay Gupta and Hetal Patel to screen many lipids for VacA binding and found that the toxin readily attached to the lipid, called sphingomyelin, which is an important and abundant component of the membrane of some animal cells.

After entering cells, VacA initiates the formation of giant vacuoles, which are easy to spot under a microscope and provide a useful indicator of VacA activity in the cell.

In order to test whether sphingomyelin was a receptor for VacA, Gupta treated cultured human cells with an enzyme that depleted the membranes of sphingomyelin.

They observed that the toxin lost its ability to cross into the cells and the giant vacuoles disappeared in the sphingomyelin-depleted cells. When he restored sphingomyelin to the same cell membranes (again, in the presence of VacA), the vacuoles returned.

"This is the first example of a bacterial virulence factor that uses sphingomyelin as a receptor. Only sphingomyelin confers sensitivity to the toxin in these cells, whereas other common membrane lipids do not," Blanke said.

It was recently found that Sphingomyelin has the ability to cluster into specialized membrane islands, or rafts, that look like raised platforms on the cell surface. In the current study, it was discovered that VacA preferentially binds to and enters the cell by means of these sphingomyelin rafts.

"Our model is that these platforms serve as the entry portals for the toxin into the cell. We think that sphingomyelin is important because it seems to cluster the toxin in these portals of entry. This seems to be absolutely essential for toxin activity," Blanke said.  

He added: "Identifying toxin receptors is important because they are outstanding targets for new drugs to block the action of toxins on human cells."

The study appears in PLoS Pathogens, a journal of the Public Library of Science.

Source: ANI

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