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What are bacterial toxins?|Toxic Effect|Beneficial Uses

What are Bacterial Toxins?

Bacterial Toxin are poisonous substance that is a specific product of the metabolic activities of a living organism and is usually very unstable, notably toxic when introduced into the tissues, and typically capable of inducing antibody formation.

➢ Bacterial Toxins produced by bacteria are generally classified into two groups: exotoxins and endotoxins.

Exotoxins:

• Exotoxins are heat-labile proteins that are produced by several Gram-positive and Gram-negative bacteria.

• These are bacterial products, which are secreted into tissues and directly harm tissues
However some exotoxins accumulate inside the cell and are either injected directly into the host or are released by cell lysis.
The genes coding for these proteins are frequently encoded on a plasmid or on bacteriophage DNA.
Some important toxins encoded by plasmids are tetanus toxin of C. tetani and heat-labile and heat-stable toxins of enterotoxigenic E. coli.
➢ Toxins encoded by bacteriophage DNA are cholera toxins, diphtheria toxins, and botulinum toxin.
➢ Exotoxins can be converted to toxoids
Exotoxins treated with formaldehyde or acid or heat can be converted into toxoid.
➢ The toxoids lack toxicity but retain antigenicity.
➢ Hence, these are used in protective vaccines.
➢ Many exotoxins are dimeric, consist of A and B subunits.
➢ The B subunit generally mediates adherence of the toxin complex to a host cell receptors and aids entrance of the exotoxin into the host cell. Exotoxins are good antigens; they induce the synthesis of protective antibody called antitoxins.
➢ Some of these antitoxins are useful in the treatment of botulism, tetanus, and other diseases.
• These toxins are very specific in their mechanism of action and act at specific sites of a tissue.
• The biochemical targets of A–B toxin include ribosomes, CAMP; G transport mechanisms, and protein
Intracellular signalling (cyclic adenosine monophosphate, production); all these cause diarrhoea, loss of neuronal functions, or even death.

❖ Examples of Exotoxins:

❑ Diphtheria toxin: – single polypeptide molecule (molecular weight [MW]: 62,000).
– Has two fragments, A and B, linked together by a disulfide bond.
– Fragment B (MW: 40,700) binds to specific host cell receptors and facilitates the entry of fragment A (MW: 21,150) into the cytoplasm.
– Fragment A inhibits peptide chain elongation factor EF-2 by catalyzing a reaction that attaches an adenosine diphosphate–ribosyl group to EF-2, yielding an inactive adenosine diphosphate–ribose–EF-2 complex.

❑ Tetanospasmin (tetanus toxin): – MW: 150,000
– cleaved by a bacterial protease into two peptides (MW, 50,000 and 100,000) linked by a disulfide bond.
– binds to receptors on the presynaptic membranes of motor neurons.
– Then migrates by the retrograde axonal transport system to the cell bodies of these neurons to the spinal cord and brainstem.
– Diffuses to terminals of inhibitory cells, including both glycinergic interneurons and γ-aminobutyric
acid (GABA)–secreting
The toxin degrades synaptobrevin, a protein required for docking of neurotransmitter vesicles on the presynaptic membrane.
– Release of the inhibitory glycine and GABA is blocked, and the motor neurons are not inhibited.
– Spastic paralysis results.

❑ Botulinum toxin: – The most potent toxin known.
– It is heat-labile and is destroyed by sufficient heating.
– There are seven distinct serologic types of toxin.
– Types A, B, E, and F are most commonly associated with human disease.
– 150,000 MW protein that is cleaved into 100,000-MW and 50,000-MW proteins linked by a disulfide bond.
– Botulinum toxin is absorbed from the gut and binds to receptors of presynaptic membranes of motor neurons of the peripheral nervous system and cranial nerves.
– Proteolysis of target proteins in the neurons inhibits the acetylcholine at the synapse. – Results in lack of muscle contraction and release of Others: alpha-toxin of Clostridium perfringens, pyogenic exotoxin A of Streptococcus pyogenes, heat-stable toxins of enterotoxigenic E. cholera toxin, etc.

❑ Methods to detect Exotoxins:

o ELISA
o Animal Toxicity test
o Latex agglutination test
 o ELEKS Gel precipitation test o PCR to detect toxin coding.


Endotoxin:

• The term endotoxin was coined in 1893 by Pfeiffer.
• Produced by Gram-negative bacteria, but not by Gram-positive bacteria.
• Lipopolysaccharide (LPS) components of the outer membrane of Gramnegative bacteria.
• These form an integral part of the cell wall not actively released from the cells.
The genes that encode the enzymes that produce the LPS are present on the bacterial chromosome, but not on plasmids or bacteriophage DNA, which usually encodes the exotoxins.
• They are heat-stable, and they are released from the bacterial cell disintegration of the cell wall.
• They are weakly antigenic and do not induce, or poorly induce protective antibodies.
• Hence, their action is not neutralized by the protective antibodies.

❖ Biological activity of endotoxin:

➢ Gram-negative bacteria produce endotoxin during infection.
➢ The toxicity of endotoxin is low in comparison with exotoxins.
➢ All endotoxins usually produce the same generalized effect of fever and shock.
➢ The lipid A protein of LPS is responsible for endotoxin activities.
➢ The endotoxin binds to specific receptors, such as CD14 and TLR4, present on macrophages, B cells, and other cells.
➢ Endotoxin exerts profound biological effects on the host and may be lethal.

Biological activities of the endotoxins include the following:

– Mitogenic effects on B lymphocytes that increase resistance to viral and bacterial infections.
– Production of gamma interferon by T lymphocytes, which may enhance the antiviral state, promote the rejection of tumour cells, and activates the macrophages and natural killer cells.
– Activation of the complement cascade with the formation of C3a and C5a.
– Production and release of acute-phase cytokines, such as IL-1, TNF- (tumour necrosis factor-alpha), IL-6, IL-8 and prostaglandins
The following can be observed clinically or experimentally:
 – fever
 – Leukopenia and hypoglycemia
– hypotension and shock resulting in impaired perfusion of essential organs (eg, brain, heart, kidney)
– intravascular coagulation and death from massive organ dysfunction.
o Fever: due to the release of IL-1
o Inflammation: Activation of the alternative pathway of complement (C3a, C5a)
• Hypoglycemia: due to glycolysis in many cell types.

o Endotoxin Shock (hypotension):

– Endotoxins at low concentration induce a such protective
– However, vasodilation, and activation of immunity and inflammatory response.
response,
endotoxins are seen in the blood of patients with Gram-negative bacterial sepsis, cause a syndrome of endotoxic shock.

 Due to bradykinin and nitric oxide release.
– Leads to arteriolar and venular constriction followed by peripheral vascular dilatation, increased vascular permeability, decrease in venous return, lowered cardiac output, stagnation in the microcirculation, peripheral vasoconstriction, shock, and impaired organ, high as fever,
Endotoxic shock is characterized by fever, leukopenia,

o Disseminated intravascular coagulation:

 – a frequent complication of gram-negative bacteremia and can also occur in other infections.
– LPS activates factor XII (Hageman factor)—the first step of the intrinsic clotting system—and sets into motion the coagulation cascade, which culminates in the conversion of fibrinogen to fibrin
– At the same time, plasminogen can be activated by LPS to plasmin (a proteolytic enzyme), which can attack fibrin with the formation of fibrin split products.
– Reduction in platelet and fibrinogen levels and detection of fibrin split products are evidence of DIC.
– Heparin can sometimes prevent the lesions associated with DIC.
– LPS causes platelets to adhere to vascular endothelium and occlusion of small blood vessels, causing ischemic or hemorrhagic necrosis in various organs.

Detection of endotoxins in medical solutions:

 o Limulus lysate test
 o Rabbit pyrogenicity test

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