BSCI 424 — PATHOGENIC MICROBIOLOGY — Fall 2000

Cholera Toxin Mechanism of Action

Two Broad Classes of Bacterial Exotoxins

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

Cholera Toxin (A-5B) (Vibrio cholerae)

• Cholera toxin is chromosomally-encoded; Lysogenic phage conversion; Highly conserved genetic sequence
  
  
• 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)
  
  
• ADP-ribosylated GTP-binding protein activates adenyl cyclase resulting in an increased cyclic AMP (cAMP) level
  
  
• Profound life-threatening diarrhea (15-20 liters/day) 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
  
  
• Ultimately resulting in metabolic acidosis, hypovolemic shock and death in the absence of fluid and electrolyte replacement therapy

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