Abstract
Botulinum neurotoxin (BoNT) is produced by the anaerobic, Gram-positive bacterium Clostridium botulinum. As one of the most poisonous toxins known and a potential bioterrosism agent, BoNT is characterized by a complex mode of action comprising: internalization, translocation and proteolytic cleavage of a substrate, which inhibits synaptic exocytotic transmitter release at neuro-muscular nerve endings leading to peripheral neuroparalysis of the skeletal and autonomic nervous systems. There are seven major serologically distinct toxinotypes (A–G) of BoNT which act on different substrates. Human botulism is generally caused by BoNT/A, B and E. Due to its extreme lethality and potential use as biological weapon, botulism remains a global public health concern. Vaccination against BoNT, although an effective strategy, remains undesirable due to the growing expectation around therapeutic use of BoNTs in various pathological conditions. This review focuses on the current approaches for botulism control by immunotherapy, highlighting the future challenges while the molecular underpinnings among subtypes variants and BoNT sequences found in non-clostridial species remain to be elucidated.
Highlights
Botulinum neurotoxins (BoNTs) are among the most poisonous substances that exist, being part of the “dirty dozen” agents listed as possible bioweapons
This review focuses on the available anti-BoNTs antibodies and efforts made towards generation vaccine against botulism, including DNA- and protein-based vaccines
In addition to the use of trivalent anti-BoNT/A, B and E mixtures, toxin sequestration and clearance by monoclonal antibodies (mAbs) may be improved by enhancing their ability to bind to red blood cells (RBCs)
Summary
Botulinum neurotoxins (BoNTs) are among the most poisonous substances that exist, being part of the “dirty dozen” agents listed as possible bioweapons. Inhalational botulism was initially reported in laboratory workers and more recently in illicit drug users after intranasal use of cocaine as well as wound botulism after drug injection. All of these cause the same clinical syndrome of symmetrical cranial nerve palsies followed by descending, symmetric, flaccid paralysis of voluntary muscles as well as inhibition of secretions, which may progress to respiratory compromise and death. Like a few other non-proteolytic BoNT/B and BoNT/F toxinotypes, BoNT/E is secreted as a unique inactive chain by group II C. botulinum strains that requires activation by host proteases This process—called nicking—is associated with a 100-fold increase in toxicity [6]. Challenges posed in the future developments will be presented with a particular emphasis on projects focused on the development of recombinant antibodies to neutralize the most lethal types of BoNTs such as the AntiBotABE project
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