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Bacterial toxins are broadly divided into two general categories: exotoxins and endotoxins. Exotoxins are proteins produced inside pathogenic bacteria and are secreted into the surrounding medium, whereas endotoxins are an integral part of the bacterial cell wall and are released only during the lysis of bacteria. The symptoms caused by endotoxin of gram-negative bacteria are similar (though vary in severity) to one another. In contrast, symptoms caused by exotoxins of different bacteria are usually different. For example, a strain of Escherichia coli that produces one type of exotoxin causes watery (non-bloody) diarrhea, whereas a different strain of E.coli that produces another type of exotoxin causes bloody diarrhea. Exotoxins vs. Endotoxins (created with BioRender.com) Exotoxins Properties of Exotoxins Exotoxins are polypeptides released extracellularly as the organism grows. Exotoxins may travel from a focus of infection to a distant part of the body and cause damage. E.g., neurotoxin (botulinum toxin, tetanus toxin), enterotoxin (cholera toxin), and cytotoxin. Cytotoxin Cytotoxin acts to disrupt the structure of individual cells. Destroyed cells slough from the surface of the mucosa, leaving it raw and unprotected, which causes loss of secretory and absorptive functions of these cells. Further damage to these cells occurs due to a strong inflammatory response from the host. Some cytotoxin acts on the gastric epithelial cells causing dysentery (stool contains numerous PMNs, and blood), and pain, cramps, and tenesmus are common symptoms. A cytotoxin produced by Staphylococcus aureus named Panton-Valentine leukocidin (PVL) causes leukocyte destruction and tissue necrosis. Examples of cytotoxins-producing organisms are Clostridioides difficile, E.coli O157: H7, Staphylococcus aureus, Bacillus cereus, Haemophilus ducreyi, and Bordetella pertussis Enterotoxin Enterotoxin causes food poisoning characterized by prominent vomiting and watery, non-bloody diarrhea. They act primarily in the jejunum and upper ileum, where most fluid transport takes place. Enterotoxins alter the metabolic activity of intestinal epithelial cells, causing an outpouring of electrolytes and fluid into the lumen, resulting in profuse and watery diarrhea. A classical example of enterotoxin is the cholera toxin. Some enterotoxins act as a superantigen within the gastrointestinal tract to stimulate the release of large amounts of cytokines, stimulating the enteric nervous system to activate the vomiting center in the brain. Most enterotoxins are heat-resistant and are therefore usually not inactivated by brief cooking. Enterotoxins are also resistant to stomach acid and enzymes in the stomach and jejunum. Enterotoxin producing Organisms Clostridium perfringensStaphylococcus aureus (staphylococcal enterotoxin)Escherichia coli (heat-labile toxin and heat-stable toxin)Escherichia coli (shiga toxin or verotoxin)Vibrio cholerae (cholera toxin)Bacillus cereus Neurotoxins Botulinum is the most potent neurotoxin produced by Clostridium botulinum. The toxin prevents the release of the neurotransmitter acetylcholine at the synapse of the neuromuscular junction, causing flaccid paralysis. Tetanus toxin is a neurotoxin that prevents the release of inhibitory neurotransmitters involved in muscle relaxation. Muscle spasms and spastic paralysis occur when the inhibitory neurons are nonfunctional, and the excitatory neurons are unopposed. Exotoxins are produced by several Gram-positive and Gram-negative bacteria and are among the most toxic substances known. Many exotoxins have an A-B subunit structure; A or active subunit possesses toxic activity, andB, or binding subunit, is responsible for binding the exotoxin to specific receptors on the human cell membrane. The binding of the subunit B determines the specificity of the exotoxin. For example, botulinum toxin acts at the neuromuscular junction because the subunit B binds to specific receptors on the surface of the motor neuron at the junction. Important exotoxins that have A-B subunit structure include botulinum toxin, cholera toxin, diphtheria toxin, enterotoxin of E.coli, and tetanus toxin. Important Bacterial Exotoxins and their Mechanism of Action Mode of action of Escherichia coli and cholera toxin (Source: Ref-1) Name of ToxinMode of ActionBacillus anthracis toxinEdema factor is an adenylate cyclase; the lethal factor is a protease that cleaves MAP kinase, which is required for cell division.Botulinum toxinIt is a protease; it blocks the release of acetylcholine by proteolytic cleavage of releasing proteins.C. difficile toxinExotoxin A and B inactivate GTPases by glucosylation.Cholera toxinStimulates adenylate cyclase by ADP-ribosylationClostridium perfringens toxinsAlpha toxin is lecithinase; enterotoxin is a superantigen.Diphtheria toxinInactivates EF-2 by ADP-ribosylationEnterotoxin of Escherichia coliLabile toxin stimulates adenylate cyclase by ADP-ribosylation; stable toxin stimulates guanylate cyclase.Enterotoxin of S. aureusIt is a superantigen acting locally in the gastrointestinal tractErythrogenic toxin (streptococcal pyrogenic exotoxins)It is a superantigen of S. pyogenes. Its action is similar to toxic shock syndrome toxin of S. aureus.Pertussis toxinStimulates adenylate cyclase by ADP-ribosylation; inhibits chemokine receptor.Scalded skin syndrome toxin of S. aureusIt is a protease that cleaves desmoglein in desmosomesShiga toxin (Shigella dysenteriae and E. coli)Shiga toxin inhibits protein synthesis in enterocytes by removing adenine from 28S ribosomal RNA.Tetanus toxinBlocks release of inhibitory neurotransmitter glycine by proteolytic cleavage of releasing proteins.Toxin shock syndrome toxin (TSST) of S. aureusIt is a superantigen. It binds to class II MHC protein and T-cell receptor; induces IL-1 and IL-2. Endotoxins: Endotoxins are lipopolysaccharide, which is an integral part of the cell wall of Gram-negative bacteria. The name endotoxin is derived from the fact that these toxins are generally cell-bound and released only when the cell lyses. Properties of Endotoxins Endotoxins are integral parts of the cell walls of gram-negative rods and cocci, in contrast to exotoxins, which are actively released from the cell. Endotoxins (LPS) are released from the surface of gram-negative bacteria in small pieces of the outer membrane.Endotoxins are lipopolysaccharides (LPS), whereas exotoxins are polypeptides.The enzymes that produce LPS are encoded by genes on the bacterial chromosomes rather than plasmid or bacteriophage DNA, which usually encodes the exotoxins.The toxicity of endotoxins is low in comparison with that of exotoxins. Though variations are seen in effectiveness or severity, all endotoxins produce the same generalized effects of ever and shock. The endotoxins of gram-negative bacteria are the best-established causes of septic shock. Septic shock is one of ICU's leading causes of death and has an estimated mortality rate of 30% to 50%.Endotoxins are weakly antigenic; they induce protective antibodies so poorly that multiple episodes of toxicity can occur.No toxoids have been produced from endotoxins, and endotoxins are not used as antigens in any available vaccine. Effects of Endotoxins The biological effects of endotoxin include activation of macrophage, fever, hypotension/shock, disseminated intravascular coagulation (DIC), and complement activation. Mode of action of endotoxins (Source: Ref-1) Fever is due to the release of IL-1 (endogenous pyrogen) and IL-6, which act on the hypothalamic temperature-regulatory center). IL-1 and IL-6 are synthesized and released by macrophages. The macrophage is the major site of action of endotoxin.Hypotension, shock, and impaired perfusion of essential organs due to nitric oxide-induced vasodilation, TNF-induced increased capillary permeability, bradykinin-induced vasodilation, and increased permeability of capillaries.Endotoxin activates macrophages and increases their phagocytic ability. Endotoxin is also a polyclonal activator of B cells (but not T cells), thus increasing the production of antibodies.Endotoxin also activates the alternate pathway of the complement cascade. This results in inflammation and tissue damage.Endotoxins may also activate a coagulation cascade causing disseminated intravascular coagulation (DIC). DIC leads to the formation of petechiae and purpura, thrombosis, and tissue ischemia, resulting in the failure of vital organs. Differences between Exotoxins and Endotoxins Though various similarities exist between exotoxins and endotoxins, they differ in many aspects. For example, both exotoxins and endotoxins alone can cause symptoms without bacteria in the host. A person eating food containing preformed exotoxin can get botulism so does the person containing pyrogenic substances in the intravenous solution. The major differences between exotoxins and endotoxins are tabulated here; PropertyExotoxinsEndotoxinsBiomoleculeProteinsLipopolysaccharide-lipoprotein complex Location of genes Plasmid or bacteriophage Bacterial chromosome SourceExotoxins are released by certain Gram-positive or Gram-negative bacteria Cell wall of Gram-negative bacteria, released only after lysis of cells Heat Stability Destroyed rapidly at 60°C (except staphylococcal enterotoxin) Stable at 100°C for one hour Mode of Action (Symptoms) Specific. Either cytotoxin, enterotoxin, or neurotoxin with defined action on cells or tissues General. Fever, diarrhea, vomiting Toxicity Highly toxic, often fatal (fatal dose on the order of 1 µg) Weakly toxic, rarely fatal (fatal dose on the order of hundreds of micrograms) Immunogenicity Highly immunogenic, stimulate the production of neutralizing antibody (antitoxins) Relatively poor immunogenicity Toxoid potential/Vaccines Treatment of toxins with formaldehyde will destroy toxicity, but treated toxins remain immunogenic. Toxids are used as vaccines. No toxoid formed, and no vaccine is availableTypical diseaseTetanus, diphtheria, botulismMeningococcemia, sepsis by gram negative rods References and further readings Levinson Warren et.al. Review of Medical Microbiology and Immunology. A guide to clinical infectious diseases. MC Graw Hill Education. LANGE