Toxins

The V. cholerae enterotoxin, cholera toxin (CT), is one of the best studied bacterial toxins both in terms of structure, function and genetics. CT is comprised of one A and five B subunits and the A subunit is nicked and activated by either an endogenous V. cholerae protease or one encountered in the gut, to give the A| and A, chains which are held together via a disulfide bridge. The N-terminal A, subunit possesses the ADP-ribosylating activity which catalyzes the transfer of NAD to the Gs regulatory component of the adenylate cyclase, resulting in increased activity of the enzyme. The direct consequence of an elevation of the intracellular cAMP concentration is an increase in specific ion (primarily CI") efflux and a decrease in specific ion (primarily Na+) absorption which provides a potent osmotic driving force for the loss of water. Hence, the watery-diarrhea ensues.

Extensive genetic analysis has shown that the cholera toxin genes ctxA and ctxB exist as an operon under the control of a positive regulatory environmental sensory system which also coregulates the expression of several other virulence determinants including a critical colonization factor, the toxin-coregulated pilus (TCP). The ctxAB operon is contained within a virulence cassette associated with transposon-like repeat sequences which are capable of mediating the tandem multiplication of the operon. Under the appropriate selection conditions, such as in vivo passage, this can lead to many copies of the CT genes within the cell and consequently increased capacity to produce cholera toxin. The B subunits are essential for the secretion of CT and also provide the binding component to permit it to interact with its receptor, CM, ganglioside on the surface of the eukaryotic cell.

The genes for two other toxins, ACE (accessory cholera enterotoxin) and ZOT (zonula occludens toxin), are contained within the same virulence cassette as the CT genes. However, their functions in pathogenesis are less well-defined than CT, except that ACE has enterotoxin activity and ZOT is reported to destroy the tight junctions in the intestinal epithelium.

Other toxins have been reported in V. cholerae but the most significant is the El Tor hemolysin which has both enterotoxic (cytolytic) and cytotoxic activities. It is under different genetic control to CT and classical strains possess a small deletion within the hlyA structural gene rendering them nonhemolytic. Elimination of the hemolysin from El Tor strains markedly changes the pathology of the tissue at the site of infection, as well as the appearance of the diarrheal stool.

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