PATHOGENIC MICROBIOLOGY

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.):

  Chromosomally-encoded

  Activated by intracellular calmodulin and, like pertussis toxin, catalyzes conversion of ATP to cAMP

  Inhibits leukocyte chemotaxis and activity

  Anthrax toxin (Bacillus anthracis):

  Plasmid-encoded

  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):

  Chromosomally-encoded

  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 (G_s) 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):

  Phage-encoded

  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):

  Chromosomally-encoded

  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):

  Chromosomally-encoded

  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 (G_i) 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):

  Chromosomally-encoded

  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.):

  Phage-encoded

  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 (GD_1b)

  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)

 

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