Tables of Toxicity of Botulinum and Tetanus Neurotoxins

Rossetto, Ornella; Montecucco, Cesare

doi:10.3390/toxins11120686

Cited by 79 publications

(73 citation statements)

References 80 publications

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“…Botulinum neurotoxin (BoNT) is one of the most toxic substances known in nature and classified as a Tier 1 select agent by the Centers for Disease Control and Prevention (CDC) in the United States [ 1 , 2 , 3 ]. There are at least seven immunologically distinct serotypes of BoNT (A–G) that include more than 40 subtypes [ 4 , 5 , 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Two VHH Antibodies Neutralize Botulinum Neurotoxin E1 by Blocking Its Membrane Translocation in Host Cells

Lam

Perry

Shoemaker

et al. 2020

Toxins

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Botulinum neurotoxin serotype E (BoNT/E) is one of the major causes of human botulism, which is a life-threatening disease caused by flaccid paralysis of muscles. After receptor-mediated toxin internalization into motor neurons, the translocation domain (HN) of BoNT/E transforms into a protein channel upon vesicle acidification in endosomes and delivers its protease domain (LC) across membrane to enter the neuronal cytosol. It is believed that the rapid onset of BoNT/E intoxication compared to other BoNT serotypes is related to its swift internalization and translocation. We recently identified two neutralizing single-domain camelid antibodies (VHHs) against BoNT/E1 termed JLE-E5 and JLE-E9. Here, we report the crystal structures of these two VHHs bound to the LCHN domain of BoNT/E1. The structures reveal that these VHHs recognize two distinct epitopes that are partially overlapping with the putative transmembrane regions on HN, and therefore could physically block membrane association of BoNT/E1. This is confirmed by our in vitro studies, which show that these VHHs inhibit the structural change of BoNT/E1 at acidic pH and interfere with BoNT/E1 association with lipid vesicles. Therefore, these two VHHs neutralize BoNT/E1 by preventing the transmembrane delivery of LC. Furthermore, structure-based sequence analyses show that the 3-dimensional epitopes of these two VHHs are largely conserved across many BoNT/E subtypes, suggesting a broad-spectrum protection against the BoNT/E family. In summary, this work improves our understanding of the membrane translocation mechanism of BoNT/E and paves the way for developing VHHs as diagnostics or therapeutics for the treatment of BoNT/E intoxication.

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Section: Introductionmentioning

confidence: 99%

Two VHH Antibodies Neutralize Botulinum Neurotoxin E1 by Blocking Its Membrane Translocation in Host Cells

Lam

Perry

Shoemaker

et al. 2020

Toxins

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“… Adapted from [ 5 ], Tetanus toxin toxicity value for humans is the results of extrapolation from monkey data. IM, intramuscular; IP, intraperitoneal; INH, inhalation; IV, intravenous.…”

Section: Figurementioning

confidence: 99%

“…High concentrations (>50 ng/person) of some of these neurotoxins cause a life-threatening paralyzing disease called botulism [ 4 ]. Toxicology data are available only for a limited number of the many BoNTs so far identified and only for few vertebrate species [ 5 ]. However, considering the data limitation, there is still a scattered scheme of responses to BoNTs among different vertebrate species.…”

Section: Introductionmentioning

confidence: 99%

“…In Table 1 , LD50 values of tetanus toxin and BoNT/A and BoNT/B for different mammals are presented in relation to the LD50 mouse value. In rats as well as chickens, a mutation at the site of tetanus neurotoxin cleavage of Vesicle-Associated Membrane Protein 1 (VAMP1) leads to a complete resistance to tetanus neurotoxin whereas humans are highly sensitive to tetanus toxin ( Table 1 ; first row) [ 5 ]. Additionally, for BoNT/B, rats appear to be highly insensitive, comparably to humans, whereas rabbits seem to be highly sensitive to BoNT/B injections.…”

Section: Introductionmentioning

confidence: 99%

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The Extreme Ends of the Treatment Response Spectrum to Botulinum Toxin in Cervical Dystonia

Samadzadeh

Brauns

Hefter

2020

Toxins

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Background: The response to BoNT is not uniform; a broad spectrum of responses and side-effects usually occurs. This study aimed to show special cervical dystonia cases with therapy response very different to normal treatment course which indicate the extreme ends of therapy spectrum. Patients: Clinical data and course of treatment of five long-term treated patients with cervical dystonia out of therapy response norms are presented: a patient who was supersensitive to standard dose and has required dose adjustment to lower dose of BoNT; one patient who worsened under a standard dose, but responded excellently to twice the standard dose; one insensitive patient who responded poorly for years to a dose well above the standard dose, but responded when dose was further increased; and two patients with a totally different response pattern to BoNT/A preparation 1, but the development of a neutralizing antibody induced secondary treatment failure in both cases and a totally different response after switch to BoNT/A preparation 2. Conclusions: These five patients indicate that the response of a patient to a BoNT preparation may be unexpected. Therefore, cautious onset of BoNT therapy is recommended as well as consequent dose adjustment later on and even switch to another BoNT/A preparation when a patient has already developed NABs against BoNT/A.

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“…This process results in the classical sign of tetanus-continual excitation of the nerves. The high toxicity of TeNT is due to very fast binding to neurons and the activity of enzymes responsible for the cleavage of the necessary proteins to block neurotransmitter release with ensuing neuroparalysis[13,22,35,37].Tetanus in animalsDifferent animal species differ in their sensitivity to neurotoxins. The most susceptible species are the horse, 56 guinea pig, monkey, then sheep, mouse, goat, and human;…”

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confidence: 99%

Tetanus in Animals — Summary of Knowledge

2020

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Tetanus is a neurologic non-transmissible disease (often fatal) of humans and other animals with a worldwide occurrence. Clostridium tetani is the spore producing bacillus which causes the bacterial disease. In deep penetrating wounds the spores germinate and produce a toxin called tetanospasmin. The main characteristic sign of tetanus is a spastic paralysis. A diagnosis is usually based on the clinical signs because the detection in the wound and the cultivation of C. tetani is very difficult. Between animal species there is considerable variability in the susceptibility to the bacillus. The most sensitive animal species to the neurotoxin are horses. Sheep and cattle are less sensitive and tetanus in these animal species are less common. Tetanus in cats and dogs are rare and dogs are less sensitive than cats. Clinically two forms of tetanus have been recognized, i. e. localized and generalized. The available treatment is not specific because the toxin in neuronal cells cannot be accessed by antitoxin antibodies. The aim of the therapy is to: neutralise the unbound neurotoxin, inhibit C. tetani growth in the wound, and provide supportive care to mitigate the effects of the neurotoxin. The treatment is difficult with an unclear prognosis.

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Tables of Toxicity of Botulinum and Tetanus Neurotoxins

Cited by 79 publications

References 80 publications

Two VHH Antibodies Neutralize Botulinum Neurotoxin E1 by Blocking Its Membrane Translocation in Host Cells

Two VHH Antibodies Neutralize Botulinum Neurotoxin E1 by Blocking Its Membrane Translocation in Host Cells

The Extreme Ends of the Treatment Response Spectrum to Botulinum Toxin in Cervical Dystonia

Tetanus in Animals — Summary of Knowledge

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