Botulinum Neurotoxins as Biothreat Agents

Smith, Theresa J.; Roxas-Duncan, Virginia; Smith, Leonard A.

doi:10.4172/2157-2526.s2-003

Cited by 15 publications

(18 citation statements)

References 110 publications

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“…Mechanisms of neurotransmission are highly conserved among all synapse types (Sollner et al, 1993), supporting the hypothesis that central synapses are a relevant model for studying CNTs. Here we found that CNTs evoked SNARE protein cleavage and reduced postsynaptic detection of neurotransmission in CNS neurons at physiological concentrations.…”

Section: Discussionmentioning

confidence: 60%

“…CNT intoxication becomes life-threatening once respiratory muscles are compromised. Although post-exposure administration of antibody-based antitoxins can neutralize CNTs in the bloodstream, there are no treatments to prevent or reverse long-term paralysis once CNTs enter the neuron (Larsen, 2009;Smith et al, 2012). Since the ability to provide supportive care to paralyzed victims for long durations is limited, treatments that can reverse paralysis are urgently needed.…”

mentioning

confidence: 99%

“…Physiological intoxication of motor nerve terminals by BoNT prevents action potential-evoked neurotransmitter release as well as action potential-independent spontaneous release (Kim et al, 1984). Since SNAP-25 and Syb1/2 are essential for both forms of neurotransmission in all known synapses (Sollner et al, 1993), we hypothesized that intoxication of synaptically active cultured neurons of CNS origin would result in synaptic blockade, which can be quantified by reduced detection of postsynaptic currents. If correct, synaptic activity would therefore represent a novel, cell-based phenotypic readout of the functional endpoint of clinical intoxication.…”

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confidence: 99%

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Botulinum and Tetanus Neurotoxin-Induced Blockade of Synaptic Transmission in Networked Cultures of Human and Rodent Neurons

et al. 2015

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Clinical manifestations of tetanus and botulism result from an intricate series of interactions between clostridial neurotoxins (CNTs) and nerve terminal proteins that ultimately cause proteolytic cleavage of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins and functional blockade of neurotransmitter release. Although detection of cleaved SNARE proteins is routinely used as a molecular readout of CNT intoxication in cultured cells, impaired synaptic function is the pathophysiological basis of clinical disease. Work in our laboratory has suggested that the blockade of synaptic neurotransmission in networked neuron cultures offers a phenotypic readout of CNT intoxication that more closely replicates the functional endpoint of clinical disease. Here, we explore the value of measuring spontaneous neurotransmission frequencies as novel and functionally relevant readouts of CNT intoxication. The generalizability of this approach was confirmed in primary neuron cultures as well as human and mouse stem cell-derived neurons exposed to botulinum neurotoxin serotypes A-G and tetanus neurotoxin. The sensitivity and specificity of synaptic activity as a reporter of intoxication was evaluated in assays representing the principal clinical and research purposes of in vivo studies. Our findings confirm that synaptic activity offers a novel and functionally relevant readout for the in vitro characterizations of CNTs. They further suggest that the analysis of synaptic activity in neuronal cell cultures can serve as a surrogate for neuromuscular paralysis in the mouse lethal assay, and therefore is expected to significantly reduce the need for terminal animal use in toxin studies and facilitate identification of candidate therapeutics in cell-based screening assays.

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Section: Discussionmentioning

confidence: 60%

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confidence: 99%

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confidence: 99%

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Botulinum and Tetanus Neurotoxin-Induced Blockade of Synaptic Transmission in Networked Cultures of Human and Rodent Neurons

et al. 2015

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“…Based on the molecular and cellular toxicokinetics of intoxication (15), a comprehensive therapeutic paradigm for botulism would include (a) broad-spectrum antitoxins to terminate exposure, (b) intracellular antidotes to block LC proteolysis of SNARE proteins, and (c) symptomatic treatments that enhance neuromuscular function and mitigate muscle weakness, with mechanical ventilation administered as needed to ensure survival. However, the only approved treatment for botulism is antitoxin, which neutralizes BoNTs in the bloodstream and prevents further neuronal uptake (16). Due to the profound acute toxicity of BoNT, antitoxin efficacy is critically dependent on time of administration after exposure (17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

Symptomatic treatment of botulism with a clinically approved small molecule

Vazquez-Cintron¹,

Machamer²,

Ondeck³

et al. 2020

JCI Insight

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“…The botulinum neurotoxin causes a flaccid paralysis known as botulism that can result from ingestion of the toxin (foodborne botulism) or inhalation and/or ingestion of neurotoxin-producing clostridial spores followed by colonization of the gut (infant botulism, adult toxicoinfections) or a contaminated wound (wound botulism) (Smith et al, 2012). Current therapies for botulism include human or equine antitoxins composed of combinations of serotype-specific antibodies (Arnon et al, 2006; CDC, 2010).…”

Section: Introductionmentioning

confidence: 99%

Genomic sequences of six botulinum neurotoxin-producing strains representing three clostridial species illustrate the mobility and diversity of botulinum neurotoxin genes

Smith

Hill

Xie

et al. 2015

Infection, Genetics and Evolution

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The whole genomes for six botulinum neurotoxin-producing clostridial strains were sequenced to provide references for under-represented toxin types, bivalent strains or unusual toxin complexes associated with a bont gene. The strains include three Clostridium botulinum Group I strains (CDC297, CDC 1436, and Prevot 594), a Group II C. botulinum strain (Eklund 202F), a Group IV Clostridium argentinense strain (CDC 2741), and a Group V Clostridium baratii strain (Sullivan). Comparisons of the Group I genomic sequences revealed close relationships and conservation of toxin gene locations with previously published Group I C. botulinum genomes. The bont/F6 gene of strain Eklund 202F was determined to be a chimeric toxin gene composed of bont/F1 and bont/F2. The serotype G strain CDC 2741 remained unfinished in 20 contigs with the bont/G located within a 1.15 Mb contig, indicating a possible chromosomal location for this toxin gene. Within the genome of C. baratii Sullivan strain, direct repeats of IS1182 insertion sequence (IS) elements were identified flanking the bont/F7 toxin complex that may be the mechanism of bont insertion into C. baratii. Highlights of the six strains are described and release of their genomic sequences will allow further study of unusual neurotoxin-producing clostridial strains.

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Botulinum Neurotoxins as Biothreat Agents

Cited by 15 publications

References 110 publications

Botulinum and Tetanus Neurotoxin-Induced Blockade of Synaptic Transmission in Networked Cultures of Human and Rodent Neurons

Botulinum and Tetanus Neurotoxin-Induced Blockade of Synaptic Transmission in Networked Cultures of Human and Rodent Neurons

Symptomatic treatment of botulism with a clinically approved small molecule

Genomic sequences of six botulinum neurotoxin-producing strains representing three clostridial species illustrate the mobility and diversity of botulinum neurotoxin genes

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