Clostridial Internalization

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). 

The extreme toxicity of clostridial neurotoxins (CNTs) derives from their absolute neurospecificity as well as from catalytic activity. TeTx and BoNTs bind specifically to the neuromuscular junction (NMJ) of motor neurons. The identity of the receptor(s) on the presynaptic membrane is unknown, but their extreme toxicity suggests that the binding affinity to the cognate receptor must be very high. The receptor-bound toxin is internalized at the presynaptic membrane of the NMJ and gains access to the neuronal cytosol. Here it blocks the release of acetylcholine (ACh), causing a flaccid paralysis (Simpson,... 

The major advantage of the lectins is that they are effective against all clostridial toxin serotypes (Bakry et ah, 1991). The disadvantage of using lectins to protect against BoNT is that they must be administered as pretreatments. This limitation is inherent in the basic mechanism of BoNT action thus no antagonist of surface receptor binding would be expected to be protective once BoNT is internalized and symptoms are manifested. 

Grumelli, C., Verderio, C., Pozzi, D., Rossetto, O., Montecucco, C., and Matteoli, M. 2005. Internalization and mechanism of action of clostridial toxins in neurons. Neurotoxicology 26 761-767. 

Tanner, R.S., Miller, L.M., Yang, D., 1993. Clostridium ljungdahlii sp-nov, an acetogenic species in clostridial ribosomal-RNA homology group-I. International Journal of Systematic Bacteriology 43 (2), 232—236. 

---