Characteristics of the organisms and their antigens

The Clostridia are spore-forming rod-shaped gram-positive bacteria that usually grow under anaerobic conditions. An important characteristic of these microorganisms is their ability to survive in high numbers for long periods of time in feces and soil, an ability related to the formation of spores which can be very resistant to temperature and pH extremes. Clostridia are potent pathogens in animals and humans because of their ability to release various exotoxins. Furthermore, many Clostridia species release more than one toxin and each toxin is immunologically distinct. For example, eight types of Clostridium botulinum and five types of Clostridium perfringens have been identified and each type elaborates different toxins. Many similarities exist among clostridial toxins. Amino acid homology and immunologic cross-reactivity exist between C. difficile toxins and C. sordellii lethal toxins and between tetanus toxins and botulinum B toxin, and these toxins have similar mechanisms of action. In addition, many Clostridia produce a variety of enzymes, including collagenases, proteinases, deoxy-ribonucleases, and neuraminidases, which compromise the host and increase the pathogenicity of these microorganisms.

Although most of the Clostridia toxins are large protein exotoxins with distinct biochemical proper ties and immunological characteristics, classification of these toxins based on their pharmacologic properties and cellular targets is far from complete. For the purpose of this review Clostridia toxins will be categorized according to the diseases they produce into four groups: 1) neurotoxins, represented primarily by C. tetani and C. botulinum which are associated with tetanus and botulism in humans; 2) entero-toxins, represented by C. perfringens enterotoxin produced by some strains of C. perfringens type A which mediate acute food poisoning, C. perfringens e and i toxins causing entertoxemia in sheep, calves, lambs and guinea pigs, and C. sordellii hemorrhagic toxin which is associated with diarrhea in cattle and sheep; 3) histotoxins or cytolytic toxins, represented by some of the C. perfringens toxins that are associated with gas gangrene and anaerobic cellulitis, and C. sordellii lethal toxin (LT), one of the causes of gas gangrene; and 4) cytoskeleton-altering toxins, represented by C. difficile toxins A and B, that mediate antibiotic-associated colitis and diarrhea following antibiotic intake in animals and humans, and C. botulinum C2 toxin. All cytoskeleton-altering toxins disrupt filamentous (F) actin in target cells. It should be emphasized, however, that many of these toxins have several other biological activities other than the ones listed above. For example, toxin A of C. difficile is also a potent enterotoxin that induces fluid secretion when injected into rabbit and rat intestinal loops.

An interesting topic of pathogenicity associated with clostridial toxins is the molecular mechanism by which these toxins modify properties of cellular proteins and, by altering their function, cause human disease (Table 1). Toxins are enzymes which can biochemically modify specific molecules on the plasma membrane or cytosol of target cells. Some of the C. perfringens toxins are very good examples of toxins which act on plasma membranes of cells. C. perfringens a toxin, a phospholipase C or lecithinase, cleaves lecithin in cell membranes into diglyceride and phos-phorylcholine as well as hydrolyzes cephalin and sphingomyelin. C. perfringens k toxin is a colla-genase, whereas the |x toxin is a hyaluronidase.

A major breakthrough in our understanding of the pathogenesis of tetanus and botulism has been the recent identification of the molecular mechanism by which C. tetanus and C. botulinum B toxins cause paralysis. Botulinum neurotoxins act on peripheral motor nerves to block acetylcholine release at neuromuscular junctions, thereby causing muscle paralysis (flaccid paralysis). On the other hand tetanus neurotoxin acts on the central nervous system by blocking neurotransmitter release from inhibitory neurons causing muscle spasms (spastic paralysis). Although these two diseases have different clinical symptoms it is now known that botulinum B and tetanus neurotoxins have identical mechanism in intoxicating nerve cells. Both toxins are zinc endopeptidases that require a zinc atom for their activity and both have a similar protein structure with a receptor binding B domain and a catalytic A domain. The mechanism of action of these toxins initially involves binding to cell surface receptors and internalization into the cytosol. Once into the cell the toxins are then cleaved by proteases into active fragments which possess catalytic action. The cellular target of botulinum B and tetanus toxin is synaptobrevin, a membrane protein which is important in neurotransmitter release and associated with small synaptic vesicles. The active forms of botulinum and tetanus toxin inactivate synaptobrevin by cleaving it at a specific peptide site.

Another important recent discovery in the field of clostridial toxins is the cellular mode of action of large clostridial toxins including C. difficile toxins A and B, and C. sordellii and C. novii toxins. The common characteristic of these toxins is their large molecular weight (>250 kDa), amino acid similarity, absence of subunits, and their similar cytopathogenic (rounding) effect on cultured cells. These toxins exert their cytopathogenic effect by modifying specific small GTP-binding proteins of the Ras superfamily that regulate cellular actin. Studies with C. difficile toxins showed that these toxins bind to specific cell receptors and are then internalized into the cytosol

Table 1 Mechanisms of some clostridial toxins

Organism

Disease

Major lethal toxins

Mechanism of toxicity

C. perfringens type A

Gas gangrene

a toxin

Cytotoxic, calcium-dependent phospholipase C

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