Botulinum Serotypes

The gene sequences that encode neurotoxins have been studied thoroughly. Depending on the C. botulinum serotype, the sequences are located on chromosomes, bacteriophages, or plasmids. Genes encoding BoNTs A, B, E... 

The accessory proteins of the progenitor toxin serve to enhance the stability of the toxin to ensure uptake from the gut. The NTNH component of the multimeric type A toxin complex is encoded by a single gene upstream of the neurotoxin locus while three different HA proteins have been characterized in association with BoNTs. All C. botulinum serotypes have been shown to produce neurotoxin complexes with the NTNH and HA proteins. 

Burnett, J.C., Ruthel, G., Stegmann, C.M., Panchal, R.G., Nguyen, T.L., Hermone, A.R., Stafford, R.G., Lane, D.J., Kenny, T.A., McGrath, C.F., Wipf, P., Stahl, A.M., Schmidt, J.J., Gussio, R., Brunger, A.T., and Bavari, S. 2007. Inhibition of metalloprotease botulinum serotype A from a pseudo-peptide binding mode to a small molecule that is active in primary neurons. J. Biol. Chem. 282 5004-5014. 

Eotuhnum neurotoxins (EoNTs) are perhaps the most lethal toxins known. EoNTs are a set of seven serotypes (A, E, C, D, E, F and G) that are produced almost exclusively by the bacteria Clostridium botulinum. Serotypes C and D are found in birds and non-human mammals. Types A, E, E and F have been implicated in human cases of botuhsm. LD50 values for EoNTs range from 1.1 to 2.5 ng/kg body weight [7]. EoNTs have been associated with a variety of foods, including honey, chili, and hash browns. Isolation of toxins from the suspected food is the current means of diagnosis. 

C. botulinum serotypes vary in their heat sensitivity. Proteolytic type B is much more heat-resistant than non-proteolytic type B, which is more heat-resistant than non-proteolytic type E (Table 6.2). 

Schiavo, G., Shone, C.C., Rossetto, O., Alexander, F.C. and Montecucco, C., Botulinum neurotoxin serotype 1 is a zinc endopeptidase specific for VAMP/ synaptobrevin, J. Biol. Chern., 268, 11516-11519, 1993. 

The effect of administering different botulinum neurotoxin serotypes at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin. Aminoglycosides Cautiously perform coadministration of botulinum toxin type A and aminoglycosides or other agents interfering with neuromuscular transmission (eg, curare-like nondepolarizing blockers, lincosamides, polymyxins, quinidine, magnesium sulfate, anticholinesterases, succinylcholine chloride) because the effect of the toxin may be potentiated. 

Clinical use of botulinum toxin. Seven strains (serotypes) of botulinum toxin have been identified,... 

Strains of C. botulinum produce seven antigenetically distinct neurotoxins designated as serotypes A through G. All seven serotypes have a similar structure and molecular weight, consisting of a heavy (H) chain and a light (L) chain joined by a disulfide bond. They all interfere with neural transmission by blocking the release of ACh (see Chapter 14), which is the principal neurotransmitter at the neuromuscular junction. 

Aoki KR (2001) A comparison of the safety margins of botulinum neurotoxin serotypes A, B, and F in mice. Toxicon 39 1815-20... 

Arndt JW, Yu W, Bi F, Stevens RC (2005) Crystal structure of botulinum neurotoxin type g light chain serotype divergence in substrate recognition. Biochemistry 44 9574-80 Arndt JW, Chai Q, Christian T, Stevens RC (2006a) Structure of botulinum neurotoxin type D light chain at 1.65 a resolution repercussions for vamp-2 substrate specificity. Biochemistry 45 3255-62... 

Breidenbach MA, Brunger AT (2004) Substrate recognition strategy for botulinum neurotoxin serotype A. Nature 432 925-9... 

Chen F, Kuziemko GM, Amersdorfer P, Wong C, Marks JD et al. (1997) Antibody mapping to domains of botulinum neurotoxin serotype A in the complexed and uncomplexed forms. Infect Immun 65 1626-30... 

Chen S, Barbieri JT (2006) Unique substrate recognition by botulinum neurotoxins serotypes A and E. J Biol Chem 281 10906-11... 

Chen S, Kim JP, Barbieri JT (2007) Mechanism of substrate recognition by botulinum neurotoxin serotype A. J Biol Chem 282 9621-27... 

Eleopra R, Tugnoli V, Rossetto O, De Grandis D, Montecucco C (1998b) Different time courses of recovery after poisoning with botulinum neurotoxin serotypes A and E in humans. Neurosci Lett 256 135-8... 

Eleopra R, Tugnoli V, Quatrale R, Gastaldo E, Rossetto O et al. (2002) Botulinum neurotoxin serotypes A and C do not affect motor units survival in humans an electrophysiological study by motor units counting. Clin Neurophysiol 113 1258-64 Eleopra R, Tugnoli V, Quatrale R, Rossetto O, Montecucco C (2004) Different types of botulinum toxin in humans. Mov Disord 19 Suppl 8 S53-9... 

Smith TJ, Lou J, Geren IN, Forsyth CM, Tsai R et al. (2005) Sequence variation within botulinum neurotoxin serotypes impacts antibody binding and neutralization. Infect Immun 73 5450-7 Son YJ, Thompson WJ (1995) Schwann cell processes guide regeneration of peripheral axons. Neuron 14 125-32... 

The natural epidemiology of foodbome botulism provides additional insight into the similarities and discrepancies between the human disease and that represented in various animal models. In the USA, around 25% of reported human botulism cases are classified as foodbome and 72% are infant (Mackle et al., 2001). Human type A and B foodbome botulism cases occur worldwide and constitute the vast majority of reported human intoxications (Maselli, 1998). The majority of other botulism cases are attributed to serotype E and are typically associated with the consumption of contaminated seafood. Generalizations have been made regarding the geographic distribution of the most common C. botulinum strains within the USA. Most human foodbome botulism outbreaks occurring west of the Mississippi are due to type A toxin type B strains are more prevalent east of the Mississippi while type E strains are typically isolated to Alaska and the Pacific Northwest (Amon et al, 2001 Richardson et al, 2004). 

In addition to nonhuman primates, most other animal species that show some sensitivity to botulinum intoxication are in fact susceptible to toxin serotypes Cl and D. Several rodent species are susceptible to oral intoxication with most botulinum toxins, including types Cl and D (Matveev, 1959 ... 

The current Centers for Disease Control and Prevention (CDC) therapy for the public is an FDA-approved, bivalent, botulinum equine antitoxin against serotypes A and B. The trivalent antitoxin against types A, B, and E is no longer available. In cases of exposure to any of the other botulinum toxin serotypes, the US Army can provide an investigational heptavalent (ABCDEFG) equine antitoxin, but the time required for typing a toxin subtype would limit its effectiveness in such cases as an outbreak. A parenteral vaccine against the toxin is currently available, but the need exists for newer nonparenteral vaccines that could be administered orally or via inhalation. 

Hilmas, C.J., Deshpande, S.S, Adler, M. (2006a). Evaluation of an appropriate animal model involving mouse, guinea pig, rat, and rabbit muscle for testing future therapeutics against botulinum neurotoxin (BoNT) a comparative study of skeletal muscle sensitivity to BoNT serotypes A, B, and E. National Biodefense Analysis and Countermeasures Center (NBACC) Technical Report. 

Schiavo, G., Rossetto, O., Catsicas, S., Polverino de Laureto, P., DasGupta, B.R., Benfenati, F., Montecucco, C. (1993a). Identification of the nerve terminal targets of botulinum neurotoxin serotypes A, D, and E. J. Biol. Chem. 268 23784-7. 

Botulimun toxin is derived from the gram-negative bacterium Clostridium botulinum, an anaerobic rod that is commonly known as the source of an extremely harm-fiil food-borne toxin. Although a number of different serotypes of toxin have been identified, serotype A is used in the commercially available drug Botox, or Oculinum. It is a high-molecular-weight protein that is supplied in a freeze-dried form requiring reconstitution with saline before injection. 

Schiavo G, Poulain B, Rossetto O, Benfenati F, Tauc L, Montecucco C (1992 b) Tetanus toxin is a zinc protein and its inhibition of neurotrasmitter release and protease activity depend on zinc. In EMBOJ. 11 3577-83 Schiavo G, Rossetto O, Santucci A, DasGupta BR, Montecucco C (1992 c) Botulinum neurotoxins are zinc proteins. In J. Biol. Chem. 267 23479-83 Schiavo G, Rossetto O, Catsicas S, Polverino de Laureto P, DasGupta BR, Benfenati F, Montecucco C (1993 a) Identification of the nerve-terminal targets of botulinum neurotoxins serotypes A, D and E. In J. Biol. Chem. 268 23784-7 Schiavo G, Santucci A, DasGupta BR, Metha PP, Jontes J, Benfenati F, Wilson MC, Montecucco C (1993 b) Botulinum neurotoxins serotypes A and E cleave SNAP-25 at distinct COOH-terminal peptide bonds. In FEBS Lett. 335 99-103 Schiavo G, Shone CC, Rossetto O, Alexandre FCG, Montecucco C (1993 c) Botulinum neurotoxin serotype F is a zinc endopeptidase specific for VAMP/synOp-tobrevin. In J. Biol. Chem. 268 11516-9... 

Schiavo G, Santucci A, DasGupta BR et al. (1993b) Botulinum neurotoxins serotypes A and E cleave SNAP-25 at distinct COOH-terminal peptide bonds. FEBS Lett 335 99-103. 

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