Toxins of Cholera

Vibrio cholerae produces several toxins: an enterotoxin, the zona occludens toxin (zot) and the accessory cholera enterotoxin (ace). The role of the two latter toxins is unclear. The enterotoxin of V. cholerae consists of 2 parts: A (active) and B (binding). The polypeptides of part B (a pentamer of five identical subunits) bind to a receptor (G_m1 ganglioside, a glycolipid ) on the epithelium of the small intestine, after which part A (a monomer) can penetrate the cell. The latter protein binds covalently to an intracellular protein (G_s-protein; s for stimulatory) which irreversibly activates it, leading to the persistent stimulation of another intracellular enzyme, adenylate cyclase. This latter enzyme promotes an increase in the intracellular cyclic-AMP, which inhibits salt absorption and promotes active chloride excretion. Water and potassium bicarbonate passively follow the chloride. In the end there is an overall water loss to the intestinal lumen. The colon cannot absorb the large amount of fluid quickly enough and diarrhoea follows. The toxic A-subunit also has other effects such as disturbing the expression of some genes, increasing inflammatory cytokines and inhibiting antigen presentation by macrophages. On the other hand, the B-subunits of cholera toxin have anti-inflammatory properties. These are under intense study at present for possible therapeutic use in immune abnormalities.

The in-vivo mechanism is probably more complicated. Cholera toxin also stimulates the nervous system in the intestinal wall (myenteric plexus), resulting in the release of 5-hydroxytryptamine (serotonin) from the enterochromaffin cells. This results in additional fluid loss to the lumen. Granisetron, a 5-HT3 receptor blocker, partially reverses this effect. More research is needed to determine the role of this mechanism in the physiopathology.

Category: Medical Subject Notes , Microbiology Notes