Toxins

Bacterial toxins for higher education

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Toxins are molecules secreted by bacteria that damage their host. This can aid the bacterium in proliferation and its ability to cause disease. Advantages of toxin secretion in bacteria are that they can damage epithelial cells can often release essential nutrients for bacterial growth, they can alter the immune response favourably for survival of the bacteria, or even increase adhesion to the damaged cells.

For the purpose of this site we will discuss two classes of toxins: ADP-ribosylating toxins and neurotoxins. Bacteria encode a wide array of toxins, and you can read more into this using the references provided.

ADP-ribosylating toxins

ADP-ribosylation is a post translational modification in eukaryotes whereby an ADP-ribose molecule is added to a newly synthesized protein. The role of such modifications are to modulate cellular processes. These include: DNA replication, gene expression, signal transduction and protein synthesis.

Diphtheria toxin

Diphtheria is a severe infection of the naso-pharynx caused by Corynebacterium diphtheria. Initially, it manifests itself as a sore throat, but then toxin release leads to death of the host epithelial cells and subsequently a sever inflammatory response. An aggregation of dead cells can occur leading to the formation of a pseudomembrane, blocking the larynx and potentially leading to asphyxiation.

Diphtheria toxin is extremely lethal, and only 100 nanograms are required per kilogram of bodyweight to kill us. The diphtheria toxin is synthesized as one, continuous 60 kDa protein. It is subsequently cleaved into an A subunit (21 kDa) which possesses the toxic activity of the protein and a B subunit (39 kDa) which is involved in binding of and entry into the host cell. These subunits are joined by a disulphide bond forming the two component toxin. Once secreted, the B subunit interacts with epithelial HB-EGF (heparin-binding epidermal growth factor-like growth factor) leading to internalisation of the toxin by endocytosis. This endosome then fuses with the cellular lysosome and acidifies. Acidification changes the conformation of the B subunit, allowing for insertion into the lysosomal membrane. The disulphide bond then breaks, releasing the toxin's A subunit into the epithelial cytoplasm.

Once in the cytoplasm, the NAD glycohydralase activity of the A subunit cleaves NAD (nicotinamide adenine dinucleotide) from ADP-ribose and transfers this ADP-ribose to the cellular elongation factor 2 (EF-2). EF-2 is essential for protein synthesis. Modification by diphtheria toxin inhibits this function, blocking protein synthesis and eventually killing the cell.

 

Diphtheria Toxin Mode of Action

Above- a diagrammatic representation of the diphtheria toxin's mode of action. Source: Microbial Pathogenesis, W. W. Norton & Company.

Neurotoxins

Neurotoxins act by either destroying tissues of the central nervous system, or by modifying the action of these systems. The action of neurotoxins are often mediated by the disruption of ion channels.

Botulinum toxin

Botulinum toxin is one of the major virulence determinants of the Gram-positive human pathogen Clostridium botulinum. Spores of this bacterium are often present in food, and following germination (under anaerobic conditions) they will release toxins into food. If the toxin is not heat inactivated (by cooking for example), it can enter the gut and subsequently the blood stream, eventually leading to severe symptoms such as: vomiting, slurred speech, paralysis and even death.

The toxin itself is extremely potent, and a single gram of it is estimated to have the potential to kill 1 million people! The toxin is synthesised and secreted as a single 150 kDa protein coated by an associated non-toxic protein. This second subunit is lost in the small intestine, and host proteases subsequently cleave the toxin into a 100 kDa binding subunit and a 50 kDa toxic subunit linked by a disulphide bond.

Once in the blood, the toxin targets peripheral neurones of the CNS. It binds to ganglioside receptors on the neuronal surface via the large subunit. Changes in pH at the neuronal surface mediate penetration of the membrane and passage of the small subunit into the neuron. The small subunit of the protein possesses a metalloprotease activity which cleaves components of the neuronal SNARE complex. This complex is implicated in releasing neurotransmitter. Inhibition of this release, leads to abolition of stimulatory activity of the neuron.

This lack of stimulatory activity can cause paralysis, a major side-effect of botulinum toxin administration.

Mechanisms of Botulinum Toxin.

Above - a diagrammatic representation of the mechanisms of action of botulinum toxin from Lebeda et al. (2008)

Other types of toxin

Across the different genera of bacteria their are a wide array of toxins with diverse mechanisms of action to those described above. One example of many, is pneumolysin, a toxin of the Pneumococcus which acts by damaging the host epithelium.

A comprehensive review of bacterial toxins can be found on the "textbookofbacteriology" website.


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