scholarly journals Why Are Botulinum Neurotoxin-Producing Bacteria So Diverse and Botulinum Neurotoxins So Toxic?

Toxins ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 34 ◽  
Author(s):  
Bernard Poulain ◽  
Michel Popoff
Keyword(s):  
Selection Pressure ◽  
Botulinum Neurotoxin ◽  
Cumulative Effects ◽  
Great Effort ◽  
High Potency ◽  
Limited Effect ◽  
Physiological Processes ◽  
Botulinum Neurotoxins ◽  
Environmental Bacteria ◽  
Lethal Toxins

Botulinum neurotoxins (BoNTs) are the most lethal toxins among all bacterial, animal, plant and chemical poisonous compounds. Although a great effort has been made to understand their mode of action, some questions are still open. Why, and for what benefit, have environmental bacteria that accidentally interact with their host engineered so diverse and so specific toxins targeting one of the most specialized physiological processes, the neuroexocytosis of higher organisms? The extreme potency of BoNT does not result from only one hyperactive step, but in contrast to other potent lethal toxins, from multi-step activity. The cumulative effects of the different steps, each having a limited effect, make BoNTs the most potent lethal toxins. This is a unique mode of evolution of a toxic compound, the high potency of which results from multiple steps driven by unknown selection pressure, targeting one of the most critical physiological process of higher organisms.

scholarly journals Variations in the Botulinum Neurotoxin Binding Domain and the Potential for Novel Therapeutics

Toxins ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 421 ◽  
Author(s):  
Jonathan Davies ◽  
Sai Liu ◽  
K. Acharya
Keyword(s):  
Botulinum Neurotoxin ◽  
Neuronal Cell ◽  
Binding Domain ◽  
Novel Therapeutics ◽  
Specific Targeting ◽  
Zinc Metalloprotease ◽  
Botulinum Neurotoxins ◽  
Translocation Domain ◽  
Subtype Differences

Botulinum neurotoxins (BoNTs) are categorised into immunologically distinct serotypes BoNT/A to /G). Each serotype can also be further divided into subtypes based on differences in amino acid sequence. BoNTs are ~150 kDa proteins comprised of three major functional domains: an N-terminal zinc metalloprotease light chain (LC), a translocation domain (HN), and a binding domain (HC). The HC is responsible for targeting the BoNT to the neuronal cell membrane, and each serotype has evolved to bind via different mechanisms to different target receptors. Most structural characterisations to date have focussed on the first identified subtype within each serotype (e.g., BoNT/A1). Subtype differences within BoNT serotypes can affect intoxication, displaying different botulism symptoms in vivo, and less emphasis has been placed on investigating these variants. This review outlines the receptors for each BoNT serotype and describes the basis for the highly specific targeting of neuronal cell membranes. Understanding receptor binding is of vital importance, not only for the generation of novel therapeutics but also for understanding how best to protect from intoxication.

scholarly journals Botulism (type A) in a horse - case report

2016 ◽  
Vol 85 (1) ◽  
pp. 71-76 ◽  
Author(s):  
Sevim Kasap ◽  
Hasan Batmaz ◽  
Meric Kocaturk ◽  
Frank Gessler ◽  
Serkan Catık ◽  
...  
Keyword(s):  
Botulinum Neurotoxin ◽  
Clinical Signs ◽  
Type A ◽  
Serum Samples ◽  
Specific Antibodies ◽  
Thoroughbred Horse ◽  
Botulinum Neurotoxin Type A ◽  
Botulinum Neurotoxins ◽  
First Time ◽  
Colonic Content

This paper presents the case of a six year-old, male, thoroughbred horse with clinical signs of inappetence, weakness, and incoordination when walking. Clinical examination showed that the horse staggered and leaned to the left side. Feedstuff was present inside and around its mouth. Salivation was increased and there was no reflex at the palpebrae and tongue. The horse had difficulty swallowing and the tone of its tail was reduced. Botulism was diagnosed based on the clinical signs. Antibiotic (ceftiofur) and fluid-electrolyte treatment was commenced. Next day, neostigmin was added to the horse’s treatment, and it became recumbent. The horse’s palpebral, tongue and tail reflexes returned partially after neostigmine methylsulphate treatment on the same day and it stood up on day four. However, it could not swallow anything during the whole week, so after getting permission from the owner, the horse was euthanized on day 10. Samples of the colonic content and blood serum were sent by courier to the laboratory for toxin neutralization, however, botulinum neurotoxins could not be detected. After that, serum samples from days 6 and 10 were sent to another laboratory for testing for botulinum neurotoxin antibodies by ELISA. Specific antibodies against botulinum neurotoxin type A were measured, indicating a previous, immuno-relevant contact with the toxin. This seroconversion for type A supports the clinical botulism diagnosis. Type A botulism is rarely seen in Europe and has been detected in a horse in Turkey for the first time.

scholarly journals Management of cervical dystonia with botulinum neurotoxins and EMG/ultrasound guidance

2018 ◽  
Vol 9 (1) ◽  
pp. 64-73 ◽  
Author(s):  
Anna Castagna ◽  
Alberto Albanese
Keyword(s):  
Adverse Events ◽  
Muscle Activity ◽  
Cervical Dystonia ◽  
Botulinum Neurotoxin ◽  
Current Practice ◽  
Ultrasound Guidance ◽  
Clinical Approach ◽  
Botulinum Neurotoxins ◽  
Neck Anatomy ◽  
Us Findings

Purpose of reviewWe provide a practical guide on the use of electromyography (EMG) and ultrasound (US) to assist botulinum neurotoxin (BoNT) treatment in patients with cervical dystonia (CD).Recent findingsUS and EMG guidance improve BoNT treatment in CD. Their use is particularly valuable for targeting deep neck muscles and managing complex cases. There is also evidence that adverse events are reduced when superficial or intermediate layer muscles are injected with assisted guidance.SummaryA structured clinical approach, based on functional neck anatomy, guides CD assessment and BoNT treatment. Muscles are selected according to clinical, EMG and US findings. US provides anatomical visualization, while EMG complements by detecting muscle activity. We review here the current practice for assisted treatment of CD through BoNT cycles. We also describe how to recognize and manage the main adverse events.

scholarly journals Effect of pH on the interaction of botulinum neurotoxins A, B and E with liposomes

1989 ◽  
Vol 259 (1) ◽  
pp. 47-53 ◽  
Author(s):  
C Montecucco ◽  
G Schiavo ◽  
B R Dasgupta
Keyword(s):  
Fatty Acid ◽  
Botulinum Neurotoxin ◽  
Structural Changes ◽  
Polar Region ◽  
Low Ph ◽  
Hydrophobic Core ◽  
Head Groups ◽  
Botulinum Neurotoxins ◽  
Ph Range ◽  
Lipid Interaction

The interaction of botulinum neurotoxin serotypes A, B and E with membranes of different lipid compositions was examined by photolabelling with two photoreactive phosphatidylcholine analogues that monitor the polar region and the hydrophobic core of the lipid bilayer. At neutral pH the neurotoxins interacted both with the polar head groups and with fatty acid chains of phospholipids. At acidic pHs the neurotoxins underwent structural changes characterized by a more extensive interaction with lipids. Both the heavy and light chain subunits of the neurotoxins were involved in the process. The change in the nature and extent of toxin-lipid interaction occurred in the pH range 4-6 and was not influenced by the presence of polysialogangliosides. The present data are in agreement with the idea that botulinum neurotoxins enter into nerve cells from a low pH intracellular compartment.

scholarly journals Botulinum Neurotoxin a Blocks Synaptic Vesicle Exocytosis but Not Endocytosis at the Nerve Terminal

1999 ◽  
Vol 147 (6) ◽  
pp. 1249-1260 ◽  
Author(s):  
Elaine A. Neale ◽  
Linda M. Bowers ◽  
Min Jia ◽  
Karen E. Bateman ◽  
Lura C. Williamson
Keyword(s):  
Synaptic Vesicle ◽  
Nerve Terminal ◽  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Botulinum Neurotoxin ◽  
Vesicle Membrane ◽  
Botulinum Neurotoxin A ◽  
Synaptic Vesicle Exocytosis ◽  
Vesicle Exocytosis ◽  
Botulinum Neurotoxins

The supply of synaptic vesicles in the nerve terminal is maintained by a temporally linked balance of exo- and endocytosis. Tetanus and botulinum neurotoxins block neurotransmitter release by the enzymatic cleavage of proteins identified as critical for synaptic vesicle exocytosis. We show here that botulinum neurotoxin A is unique in that the toxin-induced block in exocytosis does not arrest vesicle membrane endocytosis. In the murine spinal cord, cell cultures exposed to botulinum neurotoxin A, neither K+-evoked neurotransmitter release nor synaptic currents can be detected, twice the ordinary number of synaptic vesicles are docked at the synaptic active zone, and its protein substrate is cleaved, which is similar to observations with tetanus and other botulinal neurotoxins. In marked contrast, K+ depolarization, in the presence of Ca2+, triggers the endocytosis of the vesicle membrane in botulinum neurotoxin A–blocked cultures as evidenced by FM1-43 staining of synaptic terminals and uptake of HRP into synaptic vesicles. These experiments are the first demonstration that botulinum neurotoxin A uncouples vesicle exo- from endocytosis, and provide evidence that Ca2+ is required for synaptic vesicle membrane retrieval.

scholarly journals Immunoprecipitation of Native Botulinum Neurotoxin Complexes from Clostridium botulinum Subtype A Strains

2014 ◽  
Vol 81 (2) ◽  
pp. 481-491 ◽  
Author(s):  
Guangyun Lin ◽  
William H. Tepp ◽  
Marite Bradshaw ◽  
Chase M. Fredrick ◽  
Eric A. Johnson
Keyword(s):  
Gastrointestinal Tract ◽  
Clostridium Botulinum ◽  
Botulinum Neurotoxin ◽  
Protein Complexes ◽  
Host Strain ◽  
Mouse Serum ◽  
Content Type ◽  
Strain Nctc ◽  
Botulinum Neurotoxins ◽  
Subtype A

ABSTRACTBotulinum neurotoxins (BoNTs) naturally exist as components of protein complexes containing nontoxic proteins. The nontoxic proteins impart stability of BoNTs in the gastrointestinal tract and during purification and handling. The two primary neurotoxin complexes (TCs) are (i) TC1, consisting of BoNT, nontoxin-nonhemagglutinin (NTNH), and hemagglutinins (HAs), and (ii) TC2, consisting of BoNT and NTNH (and possibly OrfX proteins). In this study, BoNT/A subtypes A1, A2, A3, and A5 were examined for the compositions of their TCs in culture extracts using immunoprecipitation (IP). IP analyses showed that BoNT/A1 and BoNT/A5 form TC1s, while BoNT/A2 and BoNT/A3 form TC2s. AClostridium botulinumhost strain expressing recombinant BoNT/A4 (normally present as a TC2) from an extrachromosomal plasmid formed a TC1 with complexing proteins from the host strain, indicating that the HAs and NTNH encoded on the chromosome associated with the plasmid-encoded BoNT/A4. Strain NCTC 2916 (A1/silent B1), which carries both anhasilentbont/bcluster and anorfX bont/a1cluster, was also examined. IP analysis revealed that NCTC 2916 formed only a TC2 containing BoNT/A1 and its associated NTNH. No association between BoNT/A1 and the nontoxic proteins from the silentbont/bcluster was detected, although the HAs were expressed as determined by Western blotting analysis. Additionally, NTNH and HAs from the silentbont/bcluster did not form a complex in NCTC 2916. The stabilities of the two types of TC differed at various pHs and with addition of KCl and NaCl. TC1 complexes were more stable than TC2 complexes. Mouse serum stabilized TC2, while TC1 was unaffected.

scholarly journals Escalas do tempo

2021 ◽  
pp. 306-317
Author(s):  
Eric Landowski
Keyword(s):  
Great Effort ◽  
Mesoscopic Scale ◽  
Macroscopic Scale ◽  
Essential Variable ◽  
Physiological Processes ◽  
Long Duration ◽  
Singular Event ◽  
History Of ◽  
Mesoscopic Level ◽  
Different Time Scales

Viral epidemics are processes in which temporality obviously constitutes an essential variable. But different time scales must be distinguished. To see the current pandemic as a singular event is but an illusion due to the “mesoscopic” timescale we are embracing. There is a microscopic scale — that of physiological processes —, a mesoscopic scale, which only allows to see the closest evidence, and a macroscopic scale, that of the ecological determinisms which explain the emergence of the disease in the history of the relationships between species. The article focuses on the mesoscopic level and highlights some semiotic specificities of today’s experience : a temporal suspension, the threat of pure, dramatic and final discontinuity, the behavior of a virus that appears to have “intentionality”, a strong intensity coupled with a long duration, a time of exception, drawn to a final end, and a victory which will only be achieved with great effort.

scholarly journals Tables of Toxicity of Botulinum and Tetanus Neurotoxins

Toxins ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 686 ◽  
Author(s):  
Ornella Rossetto ◽  
Cesare Montecucco
Keyword(s):  
Biological Activity ◽  
Botulinum Neurotoxin ◽  
Animal Species ◽  
Vesicular Trafficking ◽  
Nerve Terminals ◽  
Molecular Tools ◽  
Botulinum Neurotoxins ◽  
Cholinergic Nerve Terminals ◽  
Metalloprotease Activity ◽  
Internal Comparison

Tetanus and botulinum neurotoxins are the most poisonous substances known, so much so as to be considered for a possible terrorist use. At the same time, botulinum neurotoxin type A1 is successfully used to treat a variety of human syndromes characterized by hyperactive cholinergic nerve terminals. The extreme toxicity of these neurotoxins is due to their neurospecificity and to their metalloprotease activity, which results in the deadly paralysis of tetanus and botulism. Recently, many novel botulinum neurotoxins and some botulinum-like toxins have been discovered. This large number of toxins differs in terms of toxicity and biological activity, providing a potential goldmine for novel therapeutics and for new molecular tools to dissect vesicular trafficking, fusion, and exocytosis. The scattered data on toxicity present in the literature require a systematic organization to be usable by scientists and clinicians. We have assembled here the data available in the literature on the toxicity of these toxins in different animal species. The internal comparison of these data provides insights on the biological activity of these toxins.

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