Shiga Toxin
Much of the pathogenicity associated with E. coli O157:H7 comes from the production of shiga toxins I and II (Stx1 and Stx2). Shiga toxin-producing E. coli (STEC) causes a condition known as hemorrhagic colitis, the source of the bloody diarrhea associated with E. coli O157:H7 infections. Shiga toxin is also responsible for hemolytic uremic syndrome (HUS). Shiga toxins derive their name from the organism where they were first classified, Shigella dysenteriae. S. dysenteriae is the cause of Shigellosis (bacillary dysentery), which, like E. coli O157:H7 infections, can cause severe, bloody diarrhea.
E. coli O157:H7 produces several serotypes of shiga toxin that are related to Stx which are called Stx1 and Stx2; there are also variants within these larger groups. Each shiga toxin itself has 6 subunits which are given the identification AB5. This means that there is one A subunit that causes the toxic effect of the protein and 5 B subunits that are all the same that bind to receptors on target cells (1).
When shiga toxin is released from an E. coli O157:H7 bacterium, it can translocate to organs other than the digestive tract such as the kidneys and central nervous system (brain and spinal cord). The ability of the shiga toxins to pass through cell barriers is possibly due to the increased permeability of the intestinal epithelial cells resulting from effects of the bodies own immune system. The body increases permeability of cell barriers so that important cells of the immune system (neutrophils/PMN’s) can reach the E. coli infection. Shiga toxin may use this opportunity to break through the walls of the digestive tract (2), enter the blood stream, and bind white blood cells for transport to locations such as the kidney or brain.
Once shiga toxin reaches a target organ such as the kidney, it binds to receptors on cell membranes known as globotriaosylceramide or GB3. The toxin is then brought inside the cell and transported to the Golgi apparatus, endoplasmic reticulum and finally to the nuclear membrane.
During this process, known as retrograde transport because it follows the route opposite of proteins produced by the cell, the A subunit is cleaved. One of the parts of subunit A, A1, is transported to the cytoplasm and cleaves an amino acid from the 60s ribosomal subunit. This prevents binding of t-RNA and thus inhibits protein synthesis. To put it in simpler terms, shiga toxin enters cells and stops the cells from producing proteins it needs to function. Without the ability to sustain its function, the cell dies through either apoptosis (programmed cell death) or necrosis (1).
By killing cells crucial for organ function, shiga toxins can have a debilitating effect on the body. Shiga toxin is the reason for the bloody diarrhea of E. coli O157:H7 infections because it kills cells of the intestine which causes bleeding and swelling. This is the case with HUS which, in the case of E. coli O157:H7 infections, results from damage to the kidneys caused by shiga toxins. Shiga toxins are also responsible for the central nervous system that is associated with severe HUS. In coordination with pro-inflammatory factors (cytokines: TNF-α, IL-1B, IL-6) shiga toxins cause damage to the endothelial cells that make up the blood-brain barrier. This barrier is extremely important and normally prevents pathogens and toxins from causing damage to the brain itself. But once damaged, there is the possibility for central nervous system damage (4).
Sources
1 Cherla RP, Lee SY, Tesh VL. 2003. Shiga toxins and apoptosis. FEMS Microbiol Let. 228: 159-166.
2 Hurley BP, Thorpe CM, Acheson DWK. 1998. Shiga toxin translocation across intestinal epithelial cells is enhanced by neutrophil transmigration. Infect Immun. 69:10: 6148-6155.
4 Eisenhauer PB, et al. 2004. Escherichia coli Shiga toxin 1 and TNF-α induce cytokine release by human cerebral microvascular endothelial cells. Microb Pathog. 36:4: 189-196.
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