Exotoxin

An exotoxin is a soluble protein excreted by a microorganism, including bacteria, fungi, algae, and protozoa. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. Both gram negative and gram positive bacteria produce exotoxins. They are highly potent and can cause major damage to the host. Exotoxins may be secreted, or, similar to endotoxins, may be released during lysis of the cell.

Most exotoxins can be destroyed by heating. They may exert their effect locally or produce systemic effects. (Nester, 2007). Well known exotoxins include the botulinum toxin produced by Clostridium botulinum, the Corynebacterium diphtheriae exotoxin which is produced during life threatening symptoms of diphtheria.

Exotoxins are susceptible to antibodies produced by the immune system, but many exotoxins are so toxic that they may be fatal to the host before the immune system has a chance to mount defenses against it (Nester, 2007).

Types
Although many exotoxins can be categorized by their mode of action on target cells, rigid classification of some toxins is not possible or appropriate.

Type I toxins: toxins that act from the cell surface
Type I toxins bind to a receptor on the cell surface and stimulate intracellular signaling pathways. Two examples are described below.

Superantigens
Superantigens are produced by several bacteria. The best characterized superantigens are those produced by the strains of Staphylococcus aureus and Streptococcus pyogenes that cause toxic shock syndrome. Superantigens bridge the MHC class II protein on antigen presenting cells with the T cell receptor on the surface of T cells with a particular Vβ chain. Consequently, up to 20% of all T cells are activated, leading to massive secretion of proinflammatory cytokines, which produce the symptoms of toxic shock.

Heat-stable enterotoxins
Some strains of E. coli produce heat-stable enterotoxins (ST), which are small peptides that are able to withstand heat treatment at 100oC. Different STs recognize distinct receptors on the cell surface and thereby affect different intracellular signaling pathways. For example, STa enterotoxins bind and activate membrane-bound guanylate cyclase, which leads to the intracellular accumulation of cyclic GMP and downstream effects on several signaling pathways. These events lead to the loss of electrolytes and water from intestinal cells.

Type II toxins: membrane damaging toxins
Membrane damaging toxins exhibit hemolysin or cytolysin activity in vitro. However, induction of cell lysis may not be the primary function of the toxins during infection. At low concentrations of toxin, more subtle effects such as modulation of host cell signal transduction may be observed in the absence of cell lysis. Membrane-damaging toxins can be divided into two categories, the channel-forming toxins and toxins that function as enzymes that act on the membrane.

Channel-forming toxins
Most channel-forming toxins, which form pores in the target cell membrane, can be classified into two families, the cholesterol-dependent toxins and the RTX toxins. Formation of pores by cholesterol-dependent cytolysins (CDC) such as the α toxin of Staphylococcus aureus requires the presence of cholesterol in the target cell. The size of the pores formed by members of this family is extremely large: 25-30 nm in diameter. A conserved 11 amino acid sequence is found at the C-terminus of all family members. Moreover, all CDCs are secreted by the type II secretion system. The exception is pneumolysin, which is released from the cytoplasm of Streptococcus pneumoniae when the bacteria lyse. Pneumolysin, Clostridium perfringens perfringolysin, and Listeria monocytogenes listeriolysin O cause specific modifications of histones in the host cell nucleus, resulting in down-regulation of several genes encoding proteins involved in the inflammatory resopnse. Histone modification does not involve the pore-forming activity of the CDCs. RTX (repeats in toxin) cytolysins can be identified by the presence of a specific tandemly-repeated nine amino acid residue sequence in the protein. The prototype RTX member is the HlyA hemolysin of E. coli.
 * Cholesterol-dependent cytolysins
 * RTX toxins

Toxins that enzymatically damage the membrane
One example is the α toxin of Clostridium perfringens, which causes gas gangrene. α toxin has phospholipase activity.

Type III toxins: intracellular toxins
Intracellular toxins must be able to gain access to the cytoplasm of the target cell to exert their effects.

AB toxins
One group of intracellular toxins is the AB toxins. The 'B'-subunit attaches to target regions on cell membranes, the 'A'-subunit enters through the membrane and possesses enzymatic function that affects internal cellular bio-mechanisms. The structure of these toxins allows for the development specific vaccines and treatments. Certain compounds can be attached to the B unit, which is not generally harmful, which the body learns to recognize, and which elicits an immune response. This allows the body to detect the harmful toxin if it is encountered later, and to eliminate it before it can cause harm to the host. Toxins of this type include cholera toxin, pertussis toxin, Shiga toxin and heat-labile enterotoxin from E. coli.

Injected toxins
Some bacteria deliver toxins directly from their cytoplasm to the cytoplasm of the target cell through a needle-like structure. The effector proteins injected by the type III secretion apparatus of Yersinia into target cells are one example.

Toxins that damage the extracellular matrix
These toxins allow the further spread of bacteria and consequently deeper tissue infections. Examples are hyaluronidase and collagenase.