Shiga toxin is a cellular weapon of mass destruction launched by bacterial killers. It's responsible for everything from dysentery to deadly outbreaks of food poisoning. Researchers now report that doses of the metal manganese neutralize the poison, possibly leading to the first treatment that halts its insidious effects.
Members of the genus Shigella and several virulent strains of Escherichia coli release the shiga toxin when they invade the body. The poison injures small blood vessels and can spur our cells to kill themselves. Eating food or drinking water contaminated by shiga-producing bacteria typically causes gastrointestinal symptoms such as bloody diarrhea, and the microbes can be lethal, often by damaging the kidneys so severely that the organs shut down. Last year, for example, an outbreak of shiga-releasing E. coli that started in Germany killed some 50 people.
One reason shiga toxin is so potent is its ability to dodge cellular defenses. Cells often shunt poisons they absorb to an organelle called the lysosome for destruction. But shiga toxin takes a detour after it invades a cell, traveling to an organelle called the Golgi apparatus and eventually settling down near the cell's protein-making machinery, which it shuts off. No treatments thwart the toxin, so doctors can only offer measures such as intravenous fluids to prevent dehydration.
But now molecular cell biologist Adam Linstedt of Carnegie Mellon University in Pittsburgh, Pennsylvania, and postdoctoral researcher Somshuvra Mukhopadhyay may have discovered one of shiga toxin's weaknesses. Earlier studies had shown that a protein called GPP130, which continually shuttles into and out of the Golgi apparatus, enables the toxin to reach the organelle. Other work revealed that doses of manganese trigger cells to destroy GPP130, indicating that the metal might disrupt delivery of the poison.
That's what happened in the test tube, Linstedt and Mukhopadhyay discovered. Shiga toxin made its way to the Golgi apparatus in control cells but not in cells dosed with manganese. Much of the wayward shiga toxin in the manganese-treated cells diverted to the lysosome and was destroyed, the researchers report online today in Science. "I was surprised that shiga toxin was so sensitive to the loss of GPP130," Linstedt says.
For cultured human cells and mice battling the toxin, manganese proved to be a lifesaver. Compared with untreated cells, for example, cells exposed to the metal typically could survive a dose of shiga toxin more than 2000 times higher. And when the researchers gave mice manganese and then injected them with shiga toxin, all of the rodents survived. Control animals, by contrast, died within 3 or 4 days of the toxin's injection, their kidneys severely damaged. "We've found a possible treatment for a toxin that is a major cause of food- and waterborne disease in the world," Linstedt says.
"I find it quite striking and exciting," says cell biologist Ludger Johannes of the Institut Curie in Paris. Microbiologist Vernon Tesh of Texas A&M Health Science Center in Bryan agrees. "I think it's a very important paper in terms of a target for intervention," he says. But both scientists fault the mouse experiments. The researchers "pretreated" the animals with manganese for 5 days before injecting them with shiga toxin. "That is a limitation for the idea of using anything like this as a therapeutic approach," Johannes says. However, Linstedt says that the goal was to demonstrate that manganese works against shiga toxin, not to nail down a particular dosing schedule. "We showed proof of principle."
Manganese's medical usefulness depends on whether patients can receive treatment in time, says pediatric endocrinologist Phillip Tarr of Washington University School of Medicine in St. Louis, Missouri. He notes that the problem that prompts most people to seek medical care, bloody diarrhea, doesn't begin until 3 or 4 days after exposure to the microbes. By this time, damage to the blood vessels has begun, but the kidneys don't usually fail for another 3 or 4 days. So there could be a window of time in which counteracting shiga toxin is beneficial, Tarr says.