Causes of CNS (Brain and Spinal Cord) Damage
Much of the damage to the central nervous system (CNS, brain and spinal cord) is caused by Shiga toxin, the toxin produced by E. coli O157:H7 that damages the kidneys and digestive tract. When Shiga toxin interacts with the endothelial cells that make up the blood-brain barrier, they, along with other immune cells called neutrophils, produce proteins called cytokines.
Cytokines are important signaling molecules of immune cells and play a major role in inflammation. Normally, cytokines are vital to combat disease, but some infectious agents have developed ways to manipulate cytokines to have damaging effects.
Normally the endothelial cells do not have many receptors for shiga toxin and remain generally unharmed. But various cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) cause the endothelial cells to produce more Gb3 receptors for Shiga toxin. Shiga toxin then enter the cells, stop protein synthesis and trigger other cytokines (IL-6 and IL-8). These cytokines, together with damage caused by Shiga toxin, causes the blood-brain barrier to become permeable to the Shiga toxin, cytokines, white blood cells and lipopolysaccharides (LPS, a component of bacterial cells walls that is also an endotoxin) (1).
In response to the foreign particles that cross the blood-brain barrier, astrocytes and microglia (support cells of the CNS) release other inflammatory cytokines which, along with the leukocytes generate apoptotic cascades which trigger neuronal cell death (2).
To summarize, Shiga toxin produced by E. coli uses the body’s own defense mechanisms to destroy the blood-brain barrier that protects the CNS from foreign particles (and proteins from the body itself that are foreign to the CNS). Cytokines, LPS, Shiga toxin and white blood cells trigger a cascade which induces apoptosis in neurons, which leads to CNS damage.
Sources:
1. Eisenhauer PB, Jacewicz MS, Conn KJ, et. al. 2004. Escherichia coli Shiga toxin 1 and TNF-α induce cytokine release by human cerebral microvascular endothelial cells. Microb Pathog. 36:189-196.
2 Takahashi K, Funata N, Ikuta F, Sato S. 2008. Neuronal apoptosis and inflammatory responses in the central nervous system of a rabbit treated with Shiga toxin-2. J Neuroinflammation. 5:1.
