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Thursday, March 12, 2009

article : Bacterial Exotoxins

Two Broad Classes of Bacterial Exotoxins

  1. Intracellular Targets: A-B dimeric (two domain) exotoxins: conform to general structural model (prototype is diphtheria toxin of Corynebacterium diphtheriae):

    Bipartite structure (B, binding; A, active): One component is a binding domain (B) associated with absorption to target cell surface and transfer of active component (A) across cell membrane; once internalized, domain (A) enzymatically disrupts cell function

    Receptor-mediated endocytosis (host cell uptake and internalization of exotoxin)

    ADP-ribosylation of intracellular target host molecule

  2. Cellular Targets: Cytolytic exotoxins (usually degradative enzymes) or cytolysins: hemolysis, tissue necrosis, may be lethal when administered intravenously

Three Major Types of Bacterial Cytolysins
Based on Mechanism of Action

  1. Hydrolyze membrane phospholipids (phospholipases); e.g., Clostridium; Staphylococcus

  2. Thiol(-SH)-activated cytolysins (oxygen-labile) alter membrane permeability by binding to cholesterol; e.g., streptolysin O of Streptococcus; tetanolysin of Clostridium

  3. Detergent-like activity on cell membranes; rapid rate of lysis; e.g. Staphylococcus

Examples of Two-Component (A-B) Exotoxins
with Intracellular Targets

Adenylate cyclase toxin (Bordetella spp.):
Activated by intracellular calmodulin and, like pertussis toxin, catalyzes conversion of ATP to cAMP
Inhibits leukocyte chemotaxis and activity
Anthrax toxin (Bacillus anthracis):
Three separate proteins: Protective antigen (PA); Edema factor (EF); Lethal factor (LF)
EF + PA = increase in cAMP level resulting in edema (fluid accumulation)
LF + PA = death of host cells and ultimately death of host
Botulinum toxins (7 antigenically distinct toxins (A-G)) (Clostridium botulinum):
Phage-encoded neurotoxins
Among most potent of all biological toxins
Binding domain (B-subunit) binds to neuroreceptor gangliosides on cholinergic neurons
A-subunit irreversibly inhibits release of the stimulatory neurotransmitter, acetylcholine, at myoneural (muscle-nerve) junctions (peripheral cholinergic synapses) resulting in a flaccid paralysis and death
Cholera toxin (A-5B) (Vibrio cholerae):
B-subunit binds to GM1 ganglioside receptors in small intestine
Reduction of disulfide bond in A-subunit activates A1 fragment that ADP-ribosylates guanosine triphosphate (GTP)-binding protein (Gs) by transferring ADP-ribose from nicotinamide adenine dinucleotide (NAD); the ADP-ribosylated GTP-binding protein activates adenyl cyclase resulting in an increased cyclic AMP (cAMP) level and a profound life-threatening diarrhea with profuse outpouring of fluids and electrolytes (sodium, potassium, bicarbonate) while blocking the uptake of any further sodium and chloride from the lumen of the small intestine and ultimately resulting in hypovolemic shock and death in the absence of fluid and electrolyte replacement therapy
Diphtheria toxin (A-B) (Corynebacterium diphtheria):
ADP-ribosylation inhibits cell protein synthesis by catalyzing transfer of ADP-ribose from NAD (nicotinimamide adenine nucleotide) to EF-2 (elongation factor - 2)
Exotoxin A (Pseudomonas aeruginosa):
Similar or identical to diphtheria toxin

Heat-labile enterotoxins (HLT or LT) (LT-I and LT_II) (enterotoxigenic Escherichia coli (ETEC):
LT-I is plasmid-encoded
LT-II only produced by strains isolated from animals
Similar or identical to cholera toxin

Heat-stable enterotoxins (STa and STb) (enterotoxigenic Escherichia coli (ETEC):
STa is plasmid-encoded
STb only produced by strains isolated from animals
Similar to LT-I and cholera toxin, but with increased levels of cyclic guanosine monophosphate (cGMP) leading to hypersecretion
Pertussis toxin (A-5B) (Bordetella pertussis):
S2 (B) subunit binds glycolipid receptor on ciliated respiratory cells; S3 (B) subunit binds to glycolipids on phagocytes
S1 (A) subunit inhibits signal transduction via ADP-ribosylation of GTP-hydrolyzing protein (Gi) with unregulated adenylate cyclase and increased levels of cAMP resulting in hypersecretion of respiratory secretions and mucus and paroxysmal cough
Inhibits leukocyte chemotaxis and activity
Shiga toxin (A-5B) (Shigella dysenteriae):
Among most potent of all biological toxins
B-subunit binds to Gb3 glycolipid receptor
A-subunit prevents binding of aminoacyl-transfer RNA by cleaving 28S rRNA from 60S ribosomal subunit resulting in inhibition of protein synthesis
Shiga-like toxins (A-5B) (SLT-I and SLT-II in EHEC) (enterohemorrhagic E. coli (EHEC); Shigella spp.):
SLT-I identical to S. dysenteriae Shiga toxin with the exception of a singel amino acid
SLT-II has ~60% homology with Shiga toxin
B-subunit binds to target cell glycolipid globotriaosylceramide
Similarly to cholera toxin A subunit is cleaved; A1 fragment binds to 28S rRNA of 60S ribodomal subunit and protein synthesis is inhibited
Tetanus toxin (Clostridium tetani):
Plasmid-encoded neurotoxin
Among most potent of all biological toxins released upon lysis of bacterial cell
Binding domain (B) binds to neuroreceptor gangliosides (GD1b)
A-subunit (zinc endopeptidase) is internalized and migrates from peripheral nerves to central nervous system and across synapses to pre-synaptic nerve endings (retrograde, i.e., against the normal direction of nerve impulses) where it is accumulated in vesicles and irreversibly blocks the release of inhibitory transmitters resulting in continuous stimulation of muscles by excitatory transmitters resulting in spastic paralysis (spasms of bulbar and paraspinal muscles) with trismus (lockjaw; spasms of the masticatory muscles), risus sardonicus (spasms of the masseter muscles) and opisthotonos (spasms of back and neck muscles)
Designed & Maintained by David M. Rollins
Copyright © 2000, D.M. Rollins and S.W. Joseph
Revised: September 2003

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