Structure, activity, and immune (T and B cell) recognition of botulinum neurotoxins

Botulism, which was first reported over a century ago, is caused by botulin um neurotoxins produced by Clostridium botulinum in seven immunological ser otypes (A through G). The primary structures of a number of these BoNTs hav e been determined and are reviewed here, together with their gene structure and synthesis. The biological actions of BoNTs, which result in their abil ity to block neurotransmitter release have been the subject of intensive st udy, and in this review we discuss the binding of BoNTs to the cell surface as well as the mechanism of their intercellular action. The ability of BoN Ts to block neurotransmitter release has been exploited in therapeutic appl ications to reduce muscle hyperactivity for the treatment of a variety of c linical conditions associated with involuntary muscle spasm and contraction s. The advantages, limitations, and risks of these applications are discuss ed. Certain compounds provide some limited protection against BoNT. However , more effective protection has been obtained immunologically either by pas sive immunity (i.e., by administration of anti-BoNT Abs) or by immunization with inactivated toxin. More recently, excellent protection has been obtai ned by immunization with the receptor-binding region comprising the C-termi nal (residues 860 to 1296) fragment (H-c) of the heavy chain of BoNT/A. Her e we review the mapping of the epitopes on the H-c region of BoNT/A that ar e recognized by anti-BoNT/A Abs raised in horse, human, and mouse. The epit opes on the H-c that are recognized by anti-H-c Abs and by H-c-primed T lym phocytes were mapped in two mouse strains [BALB/c (H-2(d)) and SJL (H-2(s)) ]. The peptides, which contain Ab or T cell epitopes (or both) on the H-c, were used as immunogens in BALB/c and SJL mice and we identified those pept ides whose Ab and/or T-cell responses cross-react with H-c. Identification of these peptides is an important first step in the intricate requirements for the design of a synthetic vaccine.