Shiga toxin is nasty stuff. If you are infected with a Shiga-producing bacterium, like Shigella dysenteriae or some E. coli strains, there is no clear treatment: if you are given antibiotics, your infected cells will explode, spraying the toxin all over neighboring cells and exacerbating your symptoms. Each year, 150 million people are infected with Shiga-producing bacteria, which cause dysentery and food poisoning, and a million of those die. The lack of effective treatment for such Shiga toxicosis infections is one of the main reasons this year’s outbreak of E. coli poisoning in Europe was so deadly, with more than 3,700 people infected and 45 dead. But now scientists studying how the toxin makes its way around the cell have discovered that treating mice with the metal element manganese makes them resistant to Shiga poisoning. Since manganese’s chemistry is already well understood and it’s readily available, the possibility of using it as a treatment is exciting.
Here’s how manganese blocks Shiga’s spread, according to the group’s experiments in cultured human cells:
Normally, bacterial toxins trying to gain access to your cells are intercepted and sent to be destroyed by sacs of enzymes called lysosomes. Shiga, however, hitches a ride with a normal protein called GPP130 and thus sneaks under the cell’s radar. But when manganese gets involved, it sends GPP130 on a different path through the cell and keeps it from picking up the toxin. So the Shiga toxin, waiting for its ride, gets shunted off to the lysosomes, where it gets destroyed. (To see an animation of how this works, check out the video below.) In cell culture trials, manganese improved cells’ survival of Shiga toxicosis by 3800 times, and mice given high doses of manganese leading up to exposure to Shiga toxin and continuing afterwards for several days all survived, while untreated mice sickened and died within 96 hours.
While those numbers are striking—and the mechanism the team found is a nice, tidy explanation—there are still many questions to be answered before manganese can be used for treating Shiga toxicosis in humans. First of all, there’s the question of whether humans could withstand the manganese dosage required to have this effect (manganese poisoning is its own rather unpleasant kettle of fish), and whether, surviving that, we would metabolize manganese too fast for it to work its magic. Additionally, would it work for people who are already infected? Or would it be distributed as a preventative? And of course, there is also the need to make sure that GPP130 isn’t doing anything else important: you wouldn’t want to thwart Shiga only to wind with some possibly dangerous side effect. But given the very real danger of Shiga toxicosis, testing manganese is well worth a try.
January 20th, 2012 at 8:49 pm
Even if GPP130 is important, it may be that we can do with greatly reduced levels of it for the 96-odd hours that seem to be needed to thwart the Shiga toxin. If the alternative is death then treatment to avoid death becomes imperative.
The mouse trial would seem encouraging in this regard.