Exotoxins

Abstract

Exotoxins are a group of soluble proteins that are secreted by the bacterium, enter host cells, and catalyze the covalent modification of a host cell component(s) to alter the host cell physiology. Both Gram-negative and Gram-positive bacteria produce exotoxins. A specific bacterial pathogen may produce a single exotoxin or multiple exotoxins. Each exotoxin possesses a unique mechanism of action, which is responsible for the elicitation of a unique pathology. Thus, the role of exotoxins in bacterial pathogenesis is unique to each exotoxin. Corynebacterium diphtheriae produces diphtheria toxin, which is responsible for the systemic pathology associated with diphtheria, whereas Vibrio cholerae produces cholera toxin, which is responsible for the diarrheal pathology associated with cholera. Exotoxins vary in their cytotoxic potency, with the clostridial neurotoxins being the most potent exotoxins of humans. Exotoxins also vary with respect to the host that can be intoxicated. Exotoxin A (ETA) of Pseudomonas aeruginosa can intoxicate cells from numerous species, whereas other toxins, such as diphtheria toxin, are more restricted in the species that can be intoxicated. Some bacterial toxins, such as pertussis toxin, can intoxicate numerous cell types, whereas other toxins, such as the clostridial neurotoxins, show a specific tropism and intoxicate only cells of neuronal origin. Bacterial exotoxins catalyze specific chemical modifications of host cell components, such as the ADP-ribosylation reaction catalyzed by diphtheria toxins or the deamidation reaction catalyzed by the cytotoxic necrotizing factor (CNF) produced by Escherichia coli . These chemical modifications may either inhibit or stimulate the normal action of the target molecule to yield a clinical pathology. Bacterial exotoxins possess an AB structure–function organization, in which the A domain represents the catalytic domain and the B domain comprises the receptor-binding domain and the translocation domain. The translocation domain is responsible for the delivery of the catalytic A domain into an intracellular compartment of the host cell. Many bacterial exotoxins can be chemically modified to toxoids that no longer express cytotoxicity, but retain immunogenicity. Bacterial toxins can also be genetically engineered to toxoids, which may lead to a wider range of vaccine products. Exotoxins have also been used as therapeutic agents to correct various disorders, including the treatment of muscle spasms by botulinum toxin (BT). Nontoxic forms of exotoxins have been used as carriers for the delivery of heterologous molecules to elicit an immune response and as agents in the development of cell-specific chemotherapy. In addition, bacterial toxins have been used as research tools to assist in defining various eukaryotic metabolic pathways, such as G protein-mediated signal transduction.