Neurotoxigenic Clostridia

Eric A. Johnson

doi:10.1128/9781555816513.ch56

Chapter 56 : Neurotoxigenic Clostridia

Author: Eric A. Johnson

Content Type: Reference

Publication Year: 2006

Category: Bacterial Pathogenesis

Book DOI: 10.1128/9781555816513

Chapter DOI: 10.1128/9781555816513.ch56

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Abstract:

This chapter describes the microbiological properties of Clostridium botulinum and C. tetani, with an emphasis on pathogenesis and new findings on the organisms and their clostridial neurotoxins (CNTs). Botulism is a rare but often severe paralytic disease caused by the extremely potent botulinum neurotoxins (BoNTs) produced by C. botulinum and certain other clostridia. The major treatment of botulism is supportive care, with careful attention being given to respiratory status. Tetanus is a vivid neurological disease characterized by violent and persistent spasms of the head, trunk, and limb muscles. Neurotoxigenic clostridia tend to grow as consortia, and pure cultures are often difficult to achieve and maintain. Owing to the complex nutrient requirements of neurotoxigenic clostridia, rich media are commonly used for cultivation. Bioassays are currently the most important laboratory tests used to identify neurotoxigenic clostridial species. Although BoNTs and tetanus neurotoxin (TeNT) are the primary determinants of virulence in neurotoxigenic clostridia, wound or intestinal infections also require additional virulence processes. The availability of genomic sequences and comparative genomic analyses, together with the development of genetic tools such as gene replacement and vectors for controlled gene expression, will be invaluable in elucidating pathogenic mechanisms of neurotoxigenic clostridia. To prevent further human illness and deaths by neurotoxic clostridia, antidotes are urgently needed that can reverse the detrimental effects of BoNTs and TeNT once they are bound and internalized in nerves.

Citation: Johnson E. 2006. Neurotoxigenic Clostridia, p 688-702. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch56

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Neurotoxigenic Clostridia

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FIGURE 1

A boy suffering from food-borne botulism, showing the prominent effects of BoNT on the eyes and the descending paralysis to other regions of the face. (Photograph courtesy of Charles L. Hatheway [deceased], Centers for Disease Control and Prevention, Atlanta, Ga.)

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FIGURE 1

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FIGURE 2

Morphology of C. botulinum type A cells viewed by phase-contrast microscopy. The spore-bearing cells of other serotypes of C. botulinum and C. tetani also have characterized morphologies, typically with swelling of the rod-shaped vegetative cell ( 36 ).

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FIGURE 2

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FIGURE 3

Arrangement of the genes in neurotoxin gene clusters of C. botulinum. (Diagram courtesy of Marite Bradshaw, University of Wisconsin.)

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FIGURE 3

Arrangement of the genes in neurotoxin gene clusters of C. botulinum. (Diagram courtesy of Marite Bradshaw, University of Wisconsin.)

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FIGURE 4

Proteolytic cleavage sites and basic domain structure of BoNT/A. After proteolytic activation, the NT, consisting of an L chain and an H chain, can be defined as three basic domains: (i) L chain, catalytic domain; (ii) HN, translocation domain; and (iii) HC, receptor-binding domain. As described in the text, additional proteolytic modification takes place in BoNT/A following initial cleavage. (Diagram courtesy of Marite Bradshaw, University of Wisconsin.)

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FIGURE 4

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FIGURE 5

Diagram of the three-dimensional structure of BoNT/A. The catalytic domain is located at the upper right, the translocation domain in the center, the N-terminal-binding subdomain at the left, and the C-terminal-binding domain at the lower left. The catalytic zinc is represented as a ball. The overall structure is 45 by 105 by 130 Å. (Image courtesy of Ray C. Stevens, University of California, Berkeley.)

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Tables

Neurotoxigenic Clostridia

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TABLE 1

Properties of botulinum (BoNT) and tetanus (TeNT) neurotoxins

a Gene location: C, chromosome; B, bacteriophage; P, plasmid. For putative chromosomal locations, this location is inferred from PCR amplification of chromosomal DNA preparations, except for type A, in which toxin gene mutations have been mapped to the chromosome (see references 45 and 59 ).

b Specific toxicity refers to toxins activated by trypsinization when necessary for maximum toxicity. Toxicities are per milligram of protein. Most of the reported data are from Sugiyama ( 70 ). The toxicities can vary considerably depending upon the strain, growth conditions, and other factors, and these specific activities are only representative of experiments conducted by Sugiyama ( 70 ). Studies ( 63 , 70 ) have shown that oral doses of type A or B toxin complexes in mice are 10 to 1,000 times greater than the intraperitoneal or intravenous lethal dose depending on the size of the complex, diluent, and other factors.

c The specific peptide bond cleaved is shown. However, the clostridial neurotoxins require a minimum peptide length of >14 amino acid residues, depending on the serotype and a characteristic substrate tertiary structure for catalytic activity.

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TABLE 1

Properties of botulinum (BoNT) and tetanus (TeNT) neurotoxins