Toxin That Tainted Spinach Reveals Treatment Clues

Predator or prey? The Tetrahymena (left) is approximately 50 times the size of the bacteria (right) it's trying to capture but it's entirely vulnerable to the Shiga toxin the bacteria carry in their DNA.  Image by Todd Hennessey/University at Buffalo  

A discovery by University at Buffalo biologists that may explain the evolution of a lethal toxin is providing new information that could lead to more effective treatments for humans who fall victim to it.

The toxin, known as Shiga toxin, is the same one found last year in bagged spinach that was implicated in the deaths of five people and illnesses involving hundreds more.

The UB research on "Shiga Toxin Toxicity and Resistance in Tetrahymena," presented Dec. 3, 2007 in Washington, D.C., at the annual meeting of the American Society for Cell Biology, provides the most complete picture to date of the complex biological mechanisms of bacterial viruses infected with this toxin.

"There's a difference between a bacterial virus and a human virus," said Gerald Koudelka, PhD, professor and chair in the UB Department of Biological Sciences and a co-author on the study, "and it's crucial to understanding what kind of infection you're dealing with."

Toxins like Shiga "piggyback" onto bacterial viruses, using them to become mobile, Koudelka said, while the viruses, in turn, become part of a bacterium's DNA.

"A longstanding hypothesis of this field is that toxins may have evolved to do something else besides kill mammals," said Koudelka. "Our work is the best evidence yet that that's true."

The distinction between viruses designed to kill mammals and those designed to kill bacteria should turn out to be more than a scientific novelty, Koudelka said.

With the number of bacterial viruses encoding toxins like Shiga outstripping the number of mammals by hundreds of orders of magnitude, researchers have long wondered why they are so prevalent.

To find out, the UB biologists tested the idea that they exist to ward off eukaryotic predators of bacteria like protozoa, such as Tetrahymena.

When the UB team exposed an E. coli strain that did not carry the Shiga-toxin to Tetrahymena (a eukaryote), the bacteria, predictably, were eaten.

However, when the bacteria contained the toxin-encoding virus, some were induced to produce the toxin and kill the Tetrahymena. This allowed the remaining bacteria to proliferate because there were fewer Tetrahymena eating them.

"It appears that the presence of the Tetrahymena induces toxin release by activating what is called an SOS response in the bacteria," said Todd M. Hennessey, PhD, UB professor of biological sciences and Koudelka's co-author on the research. "There are many 'danger' signals that can trigger this response and we are working on identifying the ones involved in this case."

And it has major implications for treating patients, Koudelka added. "When you give antibiotics to patients infected with the Shiga-toxin-producing bacteria, it may make them even sicker," he said. "That's because in the process of killing off the bacteria, the SOS response causes even more toxin to be released to do even more damage."

But interestingly, in the UB studies, some of the Tetrahymena exhibited resistance to the Shiga toxin.

"If we can find out how that resistance develops, then we might be able to find a treatment method that would give human cells the ability to become resistant to the toxin, too," said Hennessey.

The fact that humans appear to be innocent bystanders in a microbial war between virus-containing bacteria and their predators plays a major role in developing ways to treat patients stricken with the toxin, the researchers said.

"We have a very mammalian way of thinking about this and it's wrong,"

said Koudelka. "We are a very small part of the entire ecology of the planet and just because something can hurt us doesn't mean that's why it's there."

Co-authors on the research are William D. Lainhart and Gino Stolfa, graduate students in the Department of Biological Sciences in the UB College of Arts and Sciences.

Source: University at Buffalo