PITTSBURGH, Carnegie Mellon University researchers have discovered that an element commonly found in nature might provide a way to neutralize the potentially lethal effects of a compound known as Shiga toxin. New results published in the Jan. 20 issue of Science by Carnegie Mellon biologists Adam Linstedt and Somshuvra Mukhopadhyay show that manganese completely protects against Shiga toxicosis in animal models.
Produced by certain bacteria, including Shigella and some strains of E. coli, Shiga toxin can cause symptoms ranging from mild intestinal disease to kidney failure. The new findings could pave the way for future research aimed at creating an inexpensive treatment for infections caused by bacteria that produce the lethal Shiga toxin. Currently there is no treatment for these infections that afflict more than 150 million people each year, resulting in more than one million deaths worldwide.
Such infections are common in developing countries where they cause waterborne epidemics. The infections can be particularly deadly, especially in children, causing dysentery and severe hemorrhagic diarrhea, which cannot be adequately treated in areas without access to clean water. In developed countries, Shiga toxicosis is most common during foodborne outbreaks -- like the widespread E. coli outbreak this past summer in Germany and Western Europe, where more than 3,700 people were infected and 45 died.
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.
Produced by certain bacteria, including Shigella and some strains of E. coli, Shiga toxin can cause symptoms ranging from mild intestinal disease to kidney failure. The new findings could pave the way for future research aimed at creating an inexpensive treatment for infections caused by bacteria that produce the lethal Shiga toxin. Currently there is no treatment for these infections that afflict more than 150 million people each year, resulting in more than one million deaths worldwide.
Such infections are common in developing countries where they cause waterborne epidemics. The infections can be particularly deadly, especially in children, causing dysentery and severe hemorrhagic diarrhea, which cannot be adequately treated in areas without access to clean water. In developed countries, Shiga toxicosis is most common during foodborne outbreaks -- like the widespread E. coli outbreak this past summer in Germany and Western Europe, where more than 3,700 people were infected and 45 died.
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.
Hello. splendid job. I did not expect this. This is a splendid story. Thanks!
ReplyDeleteRed Dot Women's Ponte Seamed Pant