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.
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," said Linstedt, professor of biological sciences at Carnegie Mellon.
Serendipitous Discovery Based on Phone Call and a Protein
and Mukhopadhyay discovered exactly how Shiga toxin avoided the lysosome as they were doing basic biological research to understand how components of the cell function.
"If we weren't focused on answering fundamental biological questions, we wouldn't have made this discovery," Linstedt
Fifteen years ago Linstedt discovered GPP130, a protein found in the Golgi apparatus, a kind of post office for the cell that sorts and packages molecules made in the endoplasmic reticulum and delivers them to their final destinations within the cell.
found, didn't behave like most Golgi proteins.
Rather than remaining in the Golgi, GPP130 constantly cycles to the endosomes and back to the Golgi.
As it returns, it avoids the pathway that takes a substance to the lysosome to be degraded.
In Science, Linstedt
and Mukhopadhyay report that Shiga toxin exploits this unique quality of GPP130 to its advantage.
What I didn't realize was how profoundly dependent Shiga toxin was on GPP130," Linstedt
Because Shiga toxin was dependent on GPP130 and manganese caused loss of GPP130, Linstedt
and Mukhopadhyay decided to see whether manganese would protect against Shiga toxin infection.
In cell cultures, manganese treatment yielded an almost 4,000-fold increase in the amount of Shiga toxin required to induce cell death.
In a mouse model, mice exposed to a high dose of Shiga toxin and treated with non-toxic doses of manganese were 100 percent resistant to the toxin.
By introducing manganese, Linstedt
and Mukhopadhyay were able to remove Shiga toxin's vehicle for avoiding degradation -- GPP130.
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," Linstedt
believes that they can use manganese to block the toxin and an antibiotic to kill the bacteria, making for an extremely effective therapy.
S. Mukhopadhyay, A. D. Linstedt
Manganese Blocks Intracellular Trafficking of Shiga Toxin and Protects Against Shiga Toxicosis.
Science, 2012; 335 (6066): 332 DOI