Clostridium Receptor

Classical bacterial exotoxins, such as diphtheria toxin, cholera toxin, clostridial neurotoxins, and the anthrax toxins are enzymes that modify their substrates within the cytosol of mammalian cells. To reach the cytosol, these toxins must first bind to different cell-surface receptors and become subsequently internalized by the cells. To this end, many bacterial exotoxins contain two functionally different domains. The binding (B-) domain binds to a cellular receptor and mediates uptake of the enzymatically active (A-) domain into the cytosol, where the A-domain modifies its specific substrate (see Figure 1). Thus, three important properties characterize the mode of action for any AB-type toxin selectivity, specificity, and potency. Because of their selectivity toward certain cell types and their specificity for cellular substrate molecules, most of the individual exotoxins are associated with a distinct disease. Because of their enzymatic nature, placement of very few A-domain molecules in the cytosol will normally cause a cytopathic effect. Therefore, bacterial AB-type exotoxins which include the potent neurotoxins from Clostridium tetani and C. botulinum are the most toxic substances known today. However, the individual AB-type toxins can greatly vary in terms of subunit composition and enzyme activity (see Table 2). 

Clindamycin is a chlorine-substituted derivative of lincomycin. However it is more potent and is better absorbed from the gastrointestinal tract and has therefore replaced lincomycin in most situations. Clindamycin is in principle a bacteriostatic agent. Its indications are mainly limited to mixed anaerobic infections. As mentioned above it has a similar mechanism of action as erythromycin. It selectively inhibits bacterial protein synthesis by binding to the same 50s ribosomal subunits. Erythromycin and clindamycin can interfere with each other by competing for this receptor. Also cross-resistance with erythromycin frequently occurs. Resistance is rather chromosomal rather than plasmid mediated and is especially found in cocci and Clostridium difficile. 

Clostridium difficile has been isolated in 11-33% of patients with antibiotic-associated diarrhea, 60-75% of patients with antibiotic-associated colitis, and 96-100% of patients with pseudomembranous colitis (117,134,135). However, about 2% of the adult population are asymptomatic carriers (127). Primary symptomless colonization with C. difficile reduces the risk of antibiotic-associated diarrhea (136). Infants up to 2 years seem to be refractory to pseudomembranous colitis, although a high percentage may be carriers of C. difficile (135,137). The reasons for this are unknown. It has been speculated that infants lack receptors for the toxin. 

Laudanna C, Campbell JJ, Butcher EC (1996) Role of Rho in chemoattractant-activated leukocyte adhesion through integrins. In Science 271 981 -3 Machesky LM, Hall A (1996) Rho a connection between membrane receptor signalling and the cytoskeleton. In Trends Cell Biol. 6 304—10 Maehama T, Ohoka Y, Ohtsuka T et al. (1990) Botulinum ADP-ribosyltransferase activity as affected by detergents and phospholipids. In FEBS Lett 263 376-80 Malcolm KC, Ross AH, Qiu R-G etal. (1994) Activation of rat liver phospholipase D by the small GTP-binding protein RhoA. In J. Biol. Chem. 269 25951 -4 Moriishi K, Syuto B, Yokosawa N efal. (1991) Purification and characterization of ADP-ribosyltransferases (Exoenzyme C3) of Clostridium Botulinum type C and D strains. In J. Bacferiol. 173 6025-9... 

Simpson LL, Stiles BG, Zapeda HH et al. (1987) Molecular basis for the pathological actions of Clostridium perfringens lota toxin. In Infect. Immun. 55 118-22 Simpson LL (1989) The binary toxin produced by Clostridium botulinum enters cells by receptor-mediated endocytosis to exert its pharmacologic effects. In J. Pharmacol. Exp. Ther. 251 1223-8... 

Fritz G, Schroeder P, Aktories K (1995) Isolation and characterization of a Clostridium botulinum C2 toxin-resistant cell line Evidence for possible involvement of the cellular C2II receptor in growth regulation. In Infect Immun. 63 2334-40... 

Simpson LL (1989b) The binary toxin produced by Clostridium botulinum enters cells by receptor-mediated endocytosis to exert its pharmacologic effects. In J Pharmacol Exp Then 251 1223-8... 

Toxin B is an intracellularly acting cytotoxin and enters the cell via a receptor-mediated endocytosis pathway to reach the endosomes, from which the toxin is translocated to the cytoplasm (Florin and The-lestam, 1986 Henriques etal., 1987). Because of this specific mode of entry, the toxin concentration needed for intoxication of cells is low (lOOng/ml for about 4h). In contrast, Clostridium bofulinum exoenzyme C3 (23.5 kDa), which ADP-ribosylates the Rho subtype proteins RhoA, B and C only, enters the cells by a non-specific uptake process, possibly by pinocytosis. Therefore, C3 has to be applied in high concentrations (about 30 g/ml) for 24 h or longer. 

Nishiki t Kamata Y, Nemoto Y et al. (1994) Identification of protein receptor for Clostridium botulinum type B neurotoxin in rat brain synaptosomes. J. Biol. Chem. 269 10498-503. 

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