Approximately 150 million individuals are infected with Shiga toxin (STx)-producing Shigella bacteria or enterohemmorrhagic Escherichia coli every year and of those infected, about one million deaths result. Once inside the host, STx is released by these types of bacteria and it exerts its deadly impact by inactivating cellular ribosomes – ribosomes are the organelles within all cells that are responsible for the production of proteins. Since the synthesis of proteins within the cells is so critical to maintain the life of the cell, the symptoms of such a disorder would be wide ranging and systemic. The symptoms of shiga toxicosis include diarrhea, abdominal pain, vomiting and blood in the urine. This disease is particularly damaging to the kidneys.
For bacteria that exert their impact on human health as a result of a unique toxin such as in the case of shiga toxicosis and cholera, there must be an underlying mechanism that insures that the toxin find its way inside the target cells intact. If this pathway can be disrupted the disease process could be effectively sabotaged.
The particular pathway for STx has been elucidated. It seems that STx consists of two protein subunits A and B, where A exerts toxic effects and is bound to subunit B. Once inside the cell, this complex moves through the cellular endosomes, Golgi apparatus and the endoplasmic reticulum (ER) and finally to the cell cytoplasm where the target ribosomes are found. It also has been demonstrated that a Golgi protein, GPP130, is critical for the transport of this toxin.
Doctor Somshuvra Mukhopadhyay and his colleagues from the Department of Biological Sciences at Carnegie Melton University in Pittsburgh, PA have shown that exposure of cells in culture to 50 to 500 micromoles of Manganese (Mn) induces the degradation of GPP130. In addition, this particular effect is unique to STx – Manganese has no impact on the cholera toxin, for example. As would be expected, the cultured cells grown with Mn present, were protected from the harmful effects of STx.
If this approach works for mammalian cells in culture, one would suspect that Mn would protect whole animals from the toxin as well. In fact, mice treated with nontoxic amounts of Mn were shown to be free of disease when exposed to the lethal toxin. This an exciting finding that may prove to be of great benefit in the treatment of shiga toxicosis.