Exotoxins and Type III Cytotoxins – Bacterial Toxins

00:01 Let’s talk a bit about bacterial toxins. These are molecules produced by various bacteria that alter the normal metabolism of host cells, and they are often responsible for the major symptoms of bacterial infection. And there are many different kinds of toxins that are produced, which we will talk about briefly. Interestingly, this is in direct contrast to viral infections, in which very few viral toxins have been identified; they cause disease in very different ways from bacteria. Now we recognize different classes of bacterial toxins, some are called exotoxins, because they are secreted by the bacterium into the extracellular environment. These exotoxins shown on this picture have a typical AB structure, they have subunits, separate subunits consisting of an A component and a B component. Typically the way they work, is they are secreted by the bacterium and they bind a receptor, shown here in R, on the surface of the eukaryotic cell, on the surface of our cells. They are then taken up into the cell by the endocytic pathway, and typically the A component, which is the active component, is released from the receptor binding component, makes its way into the cytoplasm where then has its effect on cells. There is another class of toxins called the type III cytotoxins, they are shown on the right of the diagram, where we see an outline of a rod shaped bacterium and what looks like a syringe, injecting molecules into the host cell. Those are type III cytotoxins, they are directly injected into the host cell by a structure on the bacterium called a secretory injection system and these have evolved just to inject toxins into the cell. These secretory systems act by introducing molecules into cells to alter their behavior. Other toxins are produced by bacteria, that act at the surface of host cells, some of them bind to pattern recognition receptors and induce the production of cytokines, which have lethal effects, there are also pore forming toxins which make holes in cell membranes and make them die. And finally there are toxins called superantigens that bind to T cell receptors and major histocompatibility receptors, and induce the synthesis of many, many toxic cytokines. And finally there are proteins called exoenzymes produced by bacteria that modulate targets in the extracellular matrix.

02:49 Let’s look at toxins in a bit more detail. I mentioned that they typically have an AB structure. The diphtheria toxin consists of one molecule of the A and one molecule of the B, again the B is the receptor binding component, the A is the effector portion that actually has an effect on the host cell. Diphtheria toxin, the A portion blocks cell protein synthesis, the A portion ADP ribosylates, an elongation factor for translation eEF-2, it stops host cell protein synthesis and kills the cell. Cholera toxin is composed of a single A subunit and 5 B subunits. This toxin elevates intracellular cyclic adenosine monophosphate in the epithelium of the small intestine and that causes movement of fluid into the lumen and a classic diarrhea associated with cholera. And finally the Anthrax toxin, the highly lethal anthrax toxin is composed of two A and a B subunits, and again the B subunit binds the cell receptor.

03:57 Two toxins that are well known, botulinum toxin, produced by C. botulinum and tetanus toxin produced, by C. tetani clostridium, are neurotoxins. These toxins elaborated by their bacteria at different sites make their way through the circulatory system and the lymph system. Tetanus toxin for example, causes muscles to contract uncontrollably, and they cause what we call spastic paralysis.

04:25 On the other hand, botulinum toxin blocks muscle contractions, so the muscles get flaccid, this is called flaccid paralysis, so two very different effects on the central nervous system.

04:41 The type III cytotoxins we mentioned briefly before, they're shown on the right-hand part of this screen, they are injected by the bacterium into the host cell by a type III secretion apparatus. Bacteria have a number of different kinds of secretion apparati which are used to inject effector molecules into the host cell to get them to do what they want, and these have their own ways of altering the biochemistry of the cell to cause pathology.

05:10 Type III cytotoxins are found in a wide range of bacteria, for example Salmonella, Shigella, Pseudomonas, Cholera and the Plague bacilli, all produce type III toxins of various sorts and we will mention a few of these and how they work in a few moments.