Manganese Stops Deadly Shiga Toxin
Currently, the Shiga toxin is responsible for infections of about 150 million people every year, and over one million deaths annually. Shiga toxin is produced by certain species of bacteria, including several Shigella strains and E. coli strains. Symptoms can range from mild digestive discomfort to organ failure.
Shiga toxin infections are most common amongst third-world and poor countries in areas lacking water treatment. Dysentery and diarrhea are common among these areas, but the Shiga toxin is also responsible for many E. coli outbreaks, such as the outbreak of 2011 in Germany and surrounding countries.
After the Shiga toxin is secreted by bacteria, it attaches to cell membrane surface receptors. Through the receptors, it enters the cells, and begins to damage the cells’ organelles, while avoiding the cellsâ€™ lysosomes.
“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,” commented Dr. Linstedt, a professor of biological sciences at Carnegie Mellon.
Linstedt and Mukhopadhyay discovered the method of how the Shiga toxin avoided the lysosome. “If we weren’t focused on answering fundamental biological questions, we wouldn’t have made this discovery,” said Dr. Linstedt.
The key was found through the GPP130, a Golgi apparatus protein. The Shiga toxin exploits GPP130 to avoid the lysosome.
“I knew that Shiga toxin was one of the key cargo molecules that bypass the lysosome as they go from the endosome to the Golgi apparatus, so I figured it would be a good marker to study in relation to GPP130. What I didn’t realize was how profoundly dependent Shiga toxin was on GPP130,” Linstedt said.
The connection was made with the discovery by University of California’s Dr. Don Smith that GPP130 was sensitive to manganese. Further studies found that as concentrations of manganese increase within the cell, GPP130 heads straight for the lysosome, taking Shiga toxin along with it.
In Linstedt and Mukhopadhyayâ€™s in vitro studies, they found that manganese resulted in over 4,000-fold increased protection against Shiga toxin infection. Animal studies confirmed 100% protection against the Shiga toxin.
“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 â€” not a designer drug â€” is the ideal solution,” Linstedt said. “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.”
Safe levels of manganese can also be obtained from natural foods. Foods rich in manganese include spelt, garbanzo beans, spinach, pineapple, tempeh, oats, rye, and brown rice. Probiotics also produce manganese, which may provide one reason probiotics have been shown in numerous studies to protect against and treat Shiga toxin infections.
Mukhopadhyay S. Linstedt AD. Manganese Blocks Intracellular Trafficking of Shiga Toxin and Protects Against Shiga Toxicosis. Science 20 January 2012: 332-335.