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Pathogen Page

Clostridium botulinum

I. General Information

1. NCBI Taxonomy ID:

2. Disease:

Botulism

3. Introduction

The threat posed by botulism, classically a food- and waterborne disease with a high morbidity and mortality, has increased exponentially in an age of bioterrorism. Because botulinum neurotoxin (BoNT) could be easily disseminated by terrorists using an aerosol or could be used to contaminate the food or water supply, the Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases has classified it as a category A agent. In 1895, a botulism outbreak after a funeral dinner with smoked ham in the small Belgian village of Ellezelles led to the discovery of the pathogen Clostridium botulinum by Emile Pierre van Ermengem, Professor of bacteriology at the University of Ghent. The bacterium was so called because of its pathological association with the sausages (Latin word for sausage - "botulus") and not-as it was suggested-because of its shape. Modern botulinum toxin treatment was pioneered by Alan B. Scott and Edward J. Schantz. Over 100 years ago, the classic food-borne type was found to be caused by ingesting contaminated food containing the toxin produced by a bacteria. In the first half of the 20th century a second form, wound botulism, was discovered. Three additional forms (infant, hidden, and inadvertent) were first described in the last quarter of the 20th century. Botulism is today divided into 5 clinical forms: classic or food-borne botulism, infant botulism, wound botulism, hidden botulism, and inadvertent botulism. BoNTs are serologically differentiated according to their neutralization with type-specific antitoxins into seven serotypes, designated by the letters A through G. Based on the toxin type produced, C. botulinum strains are divided in groups I to IV, with groups I and II being the main human pathogens. Group I consists of proteolytic types A, B, and F, and group II consists of nonproteolytic types B, E, and F. The two groups are completely different in their phenotypical characteristics, such as temperature requirements, biochemical profile, and production of metabolites. Types C and D provoke botulism in animal species, including the avian form. All eight neurotoxins (BoNT/A to BoNT/G and TeTx (tetanus toxin)) are synthesized as a single-chain, 150,000 Da molecule which subsequently becomes nicked to the more potent dichain form, composed of a heavy (H) (approximately 100,000 Da) chain and a light (L) (50,000 Da) chain polypeptide linked by at least one disulfide bridge (PathPort).

4. Microbial Pathogenesis

The botulinum neurotoxin is a metalloproteinase that enters nerve cells and blocks neurotransmitter release by zinc-dependent cleavage of protein components of the neuroexocytosis apparatus. Specifically, botulinum toxin types A and E target a protein known as SNAP-25, and toxin types B, D, F, and G target the protein VAMP/synaptobrevin. Toxin C targets both SNAP-25 and syntaxin. Target protein cleavage significantly disrupts release of the neurotransmitter acetylcholine. In its native state, this neurotoxin is bound to nontoxic proteins, which greatly enhances toxin molecular stability. Botulinum toxin introduced into the body (potentially by a number of mechanisms but most commonly by absorption from the gastrointestinal tract) is carried throughout the body by the bloodstream. Toxin binds to nerve-ending receptors, becomes internalized within the neuron, and causes an irreversible blockade of cholinergic transmission at the following sites: all ganglionic synapses, all postganglionic parasympathetic synapses, and all neuromuscular junctions. The far-reaching results at these sites include widespread flaccid paralysis and potentially devastating autonomic nervous system perturbations (PathPort).

Link to hazard mechanism of Clostridium botulinum in HazARD.

5. Host Ranges and Animal Models

The following animal models have been established: binding of the progenitor toxins and recombinant proteins to human erythrocytes, binding experiments of the progenitor toxins and recombinant proteins to paraformaldehyde-fixed sections of guinea pig upper small intestine, wound botulism in mice using an inoculum of Clostridium botulinum type A spores, a rat model of localized disuse induced by the Clostridium botulinum toxin, and the rat as an animal model for infant botulism (PathPort).

6. Host Protective Immunity

Inhibition of BoNT action at any of the key steps of the BoNT pathogenesis process outlined above could abolish the onset of botulism. Protective antibody immune response against specific BoNT toxin types is required to protect against different BoNT toxin types in botulism infections. The administration of antitoxin is the only specific pharmacologic treatment available for botulism (Byrne et al., 2000).

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