Natural element could help fight Shiga toxin

Pittsburgh, Pa. – A commonly found element in nature might prove a valuable weapon in fighting Shiga toxins say researchers at Carnegie Mellon University.

Biologists at the university – Adam Linstedt and Somshuvra Mukhopadhyay – released the results of a study, which 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.

Future research, treatment

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, say the researchers.

Shiga toxin from Carnegie Mellon University site.

Such infections are common in developing countries where they cause waterborne epidemics. The infections can be particularly deadly, especially in children.

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.

How Shiga toxin works

The researchers say that after entering the body, Shiga toxin is secreted by the infecting bacteria. The toxin then attaches itself to a surface receptor on a cell’s plasma membrane and enters the cell through a process called endocytosis. Normally, when a harmful substance enters a cell in this way, it’s wrapped in a package called an endosome and sent directly to the cell’s lysosome where it is degraded and discarded.

“That’s exactly the process that Shiga toxin avoids. It would be neutralized if it were to get degraded, so it had to find some way to get out of being sent to the lysosome,” explains Linstedt, professor of biological sciences at Carnegie Mellon.

How manganese neutralizes

By introducing manganese, Linstedt and Mukhopadhyay were able to remove Shiga toxin’s vehicle for avoiding degradation. The researchers feel that this could be a promising treatment for neutralizing the effects of Shiga toxin in humans.

“Manganese is inexpensive. While Shiga toxin infection affects people in the developed world, it affects far more people in the developing world. An inexpensive, accessible treatment – not a designer drug – is the ideal solution,” says Linstedt.

“We know the toxicity levels of manganese in humans; we know ways to administer it. While further testing is needed to determine if manganese is a suitable treatment for humans, I’m optimistic that trials should move forward quickly.”

Future research

The researchers also believe that manganese might be able to be used in conjunction with antibiotics. Currently, if an infected person is given an antibiotic, the antibiotic kills the bacteria (E. coli or Shigella) that produce the toxin. This releases the toxin in larger amounts and causes a higher percentage of patients to die. Linstedt believes that they can use manganese to block the toxin and an antibiotic to kill the bacteria, making for an extremely effective therapy.

The Carnegie Mellon researchers plan to continue their research by using situations that more closely mimic Shiga toxin infection in humans, and by testing their antibiotic/manganese combination therapy in mouse models. The researchers also will pay attention to manganese toxicity. High doses of manganese can have severe neurotoxic effects. The amounts used in the current study were low enough that they didn’t cause any side effects in the mouse models.