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      Variability of Botulinum Toxins: Challenges and Opportunities for the Future

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          Abstract

          Botulinum neurotoxins (BoNTs) are the most potent known toxins, and are therefore classified as extremely harmful biological weapons. However, BoNTs are therapeutic drugs that are widely used and have an increasing number of applications. BoNTs show a high diversity and are divided into multiple types and subtypes. Better understanding of the activity at the molecular and clinical levels of the natural BoNT variants as well as the development of BoNT-based chimeric molecules opens the door to novel medical applications such as silencing the sensory neurons at targeted areas and dermal restoration. This short review is focused on BoNTs’ variability and the opportunities or challenges posed for future clinical applications.

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          Neurotoxins affecting neuroexocytosis.

          G Schiavo, M Matteoli, C Montecucco (2000)
          Nerve terminals are specific sites of action of a very large number of toxins produced by many different organisms. The mechanism of action of three groups of presynaptic neurotoxins that interfere directly with the process of neurotransmitter release is reviewed, whereas presynaptic neurotoxins acting on ion channels are not dealt with here. These neurotoxins can be grouped in three large families: 1) the clostridial neurotoxins that act inside nerves and block neurotransmitter release via their metalloproteolytic activity directed specifically on SNARE proteins; 2) the snake presynaptic neurotoxins with phospholipase A(2) activity, whose site of action is still undefined and which induce the release of acethylcholine followed by impairment of synaptic functions; and 3) the excitatory latrotoxin-like neurotoxins that induce a massive release of neurotransmitter at peripheral and central synapses. Their modes of binding, sites of action, and biochemical activities are discussed in relation to the symptoms of the diseases they cause. The use of these toxins in cell biology and neuroscience is considered as well as the therapeutic utilization of the botulinum neurotoxins in human diseases characterized by hyperfunction of cholinergic terminals.
          Article 0 comments Cited 216 times – based on 0 reviews     Review now
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            Botulinum toxin as a biological weapon: medical and public health management.

            S Arnon, R. Schechter, T Inglesby … (2001)
            The Working Group on Civilian Biodefense has developed consensus-based recommendations for measures to be taken by medical and public health professionals if botulinum toxin is used as a biological weapon against a civilian population. The working group included 23 representatives from academic, government, and private institutions with expertise in public health, emergency management, and clinical medicine. The primary authors (S.S.A. and R.S.) searched OLDMEDLINE and MEDLINE (1960-March 1999) and their professional collections for literature concerning use of botulinum toxin as a bioweapon. The literature was reviewed, and opinions were sought from the working group and other experts on diagnosis and management of botulism. Additional MEDLINE searches were conducted through April 2000 during the review and revisions of the consensus statement. The first draft of the working group's consensus statement was a synthesis of information obtained in the formal evidence-gathering process. The working group convened to review the first draft in May 1999. Working group members reviewed subsequent drafts and suggested additional revisions. The final statement incorporates all relevant evidence obtained in the literature search in conjunction with final consensus recommendations supported by all working group members. An aerosolized or foodborne botulinum toxin weapon would cause acute symmetric, descending flaccid paralysis with prominent bulbar palsies such as diplopia, dysarthria, dysphonia, and dysphagia that would typically present 12 to 72 hours after exposure. Effective response to a deliberate release of botulinum toxin will depend on timely clinical diagnosis, case reporting, and epidemiological investigation. Persons potentially exposed to botulinum toxin should be closely observed, and those with signs of botulism require prompt treatment with antitoxin and supportive care that may include assisted ventilation for weeks or months. Treatment with antitoxin should not be delayed for microbiological testing.
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              SV2 is the protein receptor for botulinum neurotoxin A.

              Min Dong, Felix Yeh, William Tepp … (2006)
              How the widely used botulinum neurotoxin A (BoNT/A) recognizes and enters neurons is poorly understood. We found that BoNT/A enters neurons by binding to the synaptic vesicle protein SV2 (isoforms A, B, and C). Fragments of SV2 that harbor the toxin interaction domain inhibited BoNT/A from binding to neurons. BoNT/A binding to SV2A and SV2B knockout hippocampal neurons was abolished and was restored by expressing SV2A, SV2B, or SV2C. Reduction of SV2 expression in PC12 and Neuro-2a cells also inhibited entry of BoNT/A, which could be restored by expressing SV2 isoforms. Finally, mice that lacked an SV2 isoform (SV2B) displayed reduced sensitivity to BoNT/A. Thus, SV2 acts as the protein receptor for BoNT/A.
              Article 0 comments Cited 169 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Toxins (Basel)
                Journal ID (iso-abbrev): Toxins (Basel)
                Journal ID (publisher-id): toxins
                Title: Toxins
                Publisher: MDPI
                ISSN (Electronic): 2072-6651
                Publication date (Electronic): 13 September 2018
                Publication date Collection: September 2018
                Volume: 10
                Issue: 9
                Electronic Location Identifier: 374
                Affiliations
                [1 ]Institut Pasteur, Département de Microbiologie, Unité des Toxines Bactériennes, 25 Rue du Docteur Roux, 75015 Paris, France; christine.rasetti-escargueil@ 123456pasteur.fr (C.R.-E.); emmanuel.lemichez@ 123456pasteur.fr (E.L.)
                [2 ]Université Paris Diderot, Sorbonne Paris Cité, 75205 Paris, France
                Author notes
                [* ]Correspondence: michel-robert.popoff@ 123456pasteur.fr ; Tel.: +33-145-688-307
                Article
                Publisher ID: toxins-10-00374
                DOI: 10.3390/toxins10090374
                PMC ID: 6162648
                PubMed ID: 30217070
                SO-VID: 417c66d4-5751-4e50-aab6-c2630c49f6b9
                Copyright © © 2018 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 10 August 2018
                Date accepted : 08 September 2018
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular medicine
                Keywords: botulinum neurotoxins (bonts),subtypes,bont variants
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: botulinum neurotoxins (bonts), subtypes, bont variants

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