Published by Communications and Public Affairs 519 824-4120, Ext. 56982 or 53338

News Release

August 18, 2005

Deadly Toxin Kills Through Mimicry, U of G Prof Finds

In a world first, researchers at the University of Guelph and in Denmark have discovered how one of the deadliest known toxins invades and kills human cells.

The findings by Prof. Rod Merrill of Guelph's Department of Molecular and Cellular Biology and his collaborators at the University of Aarhus were published today in Nature.

The researchers examined exotoxin A (ETA), one member of a family of powerful enzymes produced by the pathogenic bacteria that cause diseases such as cholera, diphtheria and pneumonia.

"This reveals important new insights into the virulent mechanisms of this toxin," Merrill said, adding that the knowledge will aid in the design and application of therapeutics for treatment and prevention. "It also gives us an idea of how others in this same family of enzymes attack and kill human cells."

ETA is the most potent member of this enzyme family. Scientists know that it shuts down protein synthesis in infected cells, causing rapid cell death and necrosis of the invaded tissue. However, they weren't exactly sure how the toxin went about its deadly business.

The researchers discovered that ETA invades the body by mimicking part of the ribosome, the structure within a cell that makes protein. "It's essentially a wolf in sheep's clothing," Merrill said. "It pretends to be one part of this complex so that it will be recognized and fit in. But once it's in there, it turns off the tap, so to speak, on the process of protein synthesis. The chemical reaction no longer works."

This causes problems in the host cell and eventually cell death. "If it gets out of hand, it can kill the host organism — the person — as well," Merrill said. ETA's "attack and kill" strategy also minimizes the probability of the body developing resistance, he said.

"Now that we better understand the mechanism, we can work at developing inhibitors to block the toxin's activity," Merrill said. He added that prevention and treatment of early bacterial infection are especially critical in people with compromised immune systems.

The research was conducted in Denmark using X-ray crystallography and in Guelph. The scientists produced three-dimensional structures of ETA along with its target ribosomal protein, elongation factor 2. Their work provided the most detailed understanding to date of the toxin's structural particulars.

"Two very distinct research groups came together to solve this problem," Merrill said. "On our own, neither one of us would have been able to accomplish this. Our group at Guelph was skilled in the exploration and characterization of the enzyme, and the strength of the Aarhus group was in the X-ray crystallographic analysis."

Guelph chemistry professor Adrian Schwan, along with researchers from the National Cancer Institute in Maryland, also contributed to the study.