A simple mineral supplement — manganese — holds promise as the first successful treatment for hemorrhage-inducing infections caused by some food- and waterborne germs. The mineral helps detoxify Shiga toxin, which is produced by a host of bacteria, including the type of E. coli that killed scores and sickened more than 3,700 people in Europe last year.
The new work, by researchers at Carnegie Mellon University in Pittsburgh, appears in the Jan. 20 Science.
Although the data are preliminary, “it’s an exciting finding,” says microbiologist Vernon Tesh of the Texas A&M Health Science Center in Bryan, who did not participate in the new study. Manganese might soon offer a low-cost treatment that physicians could administer “to every patient that comes into the clinic with a bloody stool,” he says.
“That would be a tremendous boon,” he adds, because although antibiotics can wipe out germs responsible for these infections, such drugs are strongly discouraged. Killing the bugs only expedites their release of Shiga toxin, increasing a patient’s risk of kidney failure, stroke and death.
The new finding “is a classic example of serendipity in science,” says coauthor Adam Linstedt, a cell biologist at Carnegie Mellon. His team has been exploring the somewhat mysterious cellular role of a protein called GPP130. Then a colleague at the University of California, Santa Cruz reported the puzzling observation that giving cells manganese made their GPP130 disappear.
Normally, foreign materials entering a cell get tasted by an internal compartment called an endosome. Endosomes then shunt undesirable substances to another compartment, a lysosome, where they will be broken down and their raw materials discarded or recycled.
That should spell the end of Shiga toxin — except it never reaches the lysosomes. Somewhere along the way, the poison hijacks protein-trafficking systems and forces a detour elsewhere in the cell. There the hijacker knocks out the cell’s life-sustaining machinery.
Linstedt and Somshuvra Mukhopadhyay, also of Carnegie Mellon, now show that it’s GPP130 that Shiga toxin hijacks. And manganese can defend GPP130 from that attack, allowing cells to shuttle the toxin directly to lysosomes, where it’s broken down into harmless components. In cells grown in a test tube and in mice, manganese pretreatment prevented death from the administration of pure Shiga toxin.
How clinically helpful that might be remains unclear. The toxin destroys the body’s smallest blood vessels, notes epidemiologist Dirk Werber of the Robert Koch Institute in Berlin. Vascular injury, which is the most dramatic consequence of infection with Shiga toxin-producing E. coli, “is likely to be well under way by the time infected patients seek medical attention for diarrhea,” he says.
That’s true, Tesh acknowledges, although up to seven days can pass between the onset of bloody diarrhea and catastrophic vascular effects, as the toxin breaks out of the gut and begins circulating. So there would probably be a brief window when manganese treatment could save lives, he says.
The Carnegie Mellon researchers are now homing in on the minimum amount of manganese needed to protect animals, and hope to soon begin testing using Shiga-toxin-producing E. coli.