EXOTOXINS

Exotoxins are heat labile proteins that are secreted by some species of bacteria and diffuse readily into the surrounding medium. In contrast to endotoxins, which are integral part of bacteria; exotoxins are actively synthesized and released. Exotoxins are produced by a variety of bacteria including gram-positive and gram-negative bacteria. In some species, most strains produce the same exotoxin while in others only a subset of strains produces a particular exotoxin. They are antigenic and can be toxoided. Their activity can be neutralized by antitoxins. Most of the toxins have enzymatic activity. Many toxins are extraordinarily powerful, small amounts can be lethal. Toxins can be separated from the culture broth by filtration. Toxin production in some bacteria are associated with lysogeny. Example:
1. Diphtheria toxin is coded by a temperate beta phage
2. Erythrogenic toxins of Streptococcus pyogenes 
3. Production of the anthrax toxin is mediated by a temperature-sensitive plasmid, pX01

Nomenclature of exotoxins:
Exotoxins which attack a variety of cell types are called cytotoxins whereas exotoxins that attack specific cell types are named according to the cell type or organ they damage such as neurotoxin, enterotoxin, leucotoxin. Exotoxins can also be named from the species, which produces them and from the disease with which they are associated. Examples include cholera toxin from Vibrio cholerae, the cause of cholera and tetanus toxin from Clostridium tetani, and the cause of tetanus. Toxins can also be named on the basis of their activities e.g. adenylate cyclase or simply given a letter e.g. exotoxin A of Pseudomonas aeruginosa.

Examples of exotoxin producing bacteria:
     � Gram positive bacteria producing exotoxins: S.aureus, B.cereus, C.tetani, C.botulinum, C.diphtheriae, S.pyogenes, B.anthracis
     � Gram negative bacteria producing exotoxins: V.cholerae, Shigella sps, Enterotoxigenic E.coli, Enteroinvasive E.coli, Enterohemorrhagic E.coli, P.aeruginosa

Classification of exotoxins based on action:

Toxins that Aid in Spreading: Toxins, which act on the extracellular matrix of connective tissue and aid in spreading the infection by breaking down extracellular matrix of connective tissue. Examples include:

• Collagenases produced by Clostridium perfringens

• Hyaluronidase produced by S.aureus and S.pyogenes

• DNAse produced by S.aureus and S.pyogenes, which thins out pus

• Collagenases and elastases produced by Clostridium perfringens

• Exfoliative toxin produced by S.aureus

Toxins that damage membranes: these toxins usually work in one of two ways: they either act as lipases and digest membrane phospholipids or form membrane pores. Examples include:

• Lecithinase(phospholipase C,alpha-toxin) produced by Clostridium perfringins

• alpha-toxin and delta-toxin of Staphylococcus aureus

• Hemolysins and leucocidin produced by S.pyogenes

Toxins that Block Protein Synthesis: Many of these have two portions, the B sub-unit, which binds to the host cell and A sub-unit which mediates the toxic activity. Examples include:

• Diphtheria toxin produced by Corynebacterium diphtheriae

• Exotoxin A produced by Pseudomonas aeruginosa

Toxins that Block Nerve Function: Interfere in neurotransmission and thereby result in spastic or flaccid paralysis. Examples include:

• Tetanus toxin (tetanospasmin) produced by Clostridium tetani

• Botulinum toxin produced by Clostridium botulinum

Enterotoxins: Most of the toxins have effect on the gut resulting in diarrhea or dysentery. Examples include:

• Cholera toxin produced by Vibrio cholerae

• Shiga toxin produced by Shigella dysenteriae

• LT and ST produced by Enterotoxigenic E.coli

• Shiga-like toxins produced by Enterohemorraghic E.coli

Other: Other toxins that have different effects include Anthrax toxin produced by Bacillus anthracis, which in turn is three components namely, edema factor, protective antigen and lethal factor.

Superantigens: These antigens bypass the natural mode of T cell activation and non-specifically stimulate large population of T lymphocytes resulting in massive immune response. Examples include:

• Toxic Shock Syndrome Toxin-1 produced by S.aureus

• Enterotoxin produced by S.aureus

• Streptococcal pyrogenic exotoxins produced by S.pyogenes

Detection of exotoxins:
      a. Since the exotoxins are proteins, various immunological techniques such as precipitation, agglutination, ELISA, RIA can be used.
      b.  Exotoxin can be demonstrated by in-vivo models using laboratory animals or tissue culture.

Significance of exotoxins:

• Most bacteria use exotoxins as virulence factors, aiding their spread and tissue damage. Some toxins actually evade immune system by damaging the cells involved in immune response or diverting immune response.

• Clostridium botulinum has potential of being used in biological warfare.

• Detection of toxin in vitro is a method of identifying the pathogenic strains from clinical specimens

• Botulinum toxin injection is used in conditions of excessive and inappropriate muscle contraction, hyperhidiosis in armpits and palms, spasticity, sphincter contraction, eye-movement disorders, tics and tremors, and cosmetically to treat facial lines and wrinkles. Injection of botulinum toxin is a new treatment option for achalasia.

• Inactivated toxins (toxoid) can be used to immunize individuals.