Cholera and whooping cough

• Describe Cholera

  Cholera is a food-borne disease caused by the gram negative bacteria Vibrio cholerae. This bacteria secretes an enterotoxin known as cholera toxin that leads sudden onset of diarrhoea, that leads to severe dehydration and a 50-60% of death. It is typically treated with fluid replacement therapy and there are vaccines that have recently become available.
• Describe V. Cholera virulence factors

  • Motility: flagellum and accessory colonisation factor gene products regulate motility
  • Neuraminidase: penetration of mucin layer
  • Adherence: toxin coregulated pili are clumped at one side of the cell
  • Cholera toxin
• Describe the action of cholera toxin on mucosal cells

  Cholera toxin causes greater movement of chloride ions out of the epithelia and into the gut lumen, as well as inhibiting movement of sodium ions into the epithelia. This increases the osmotic pressure of the gut lumen and drives movement of water into the gut.

  
• Describe the cholera toxin structure and how this relates to its binding

  Consists of two different subunits linked via disulphide bonds: subunit A and subunit B. Each toxin molecule has one subunit A and four or more B subunits. Subunit B is inactive but binds to GM1 ganglioside on mucosal cell surface and subunit A does not bind to cell membranes and is slightly toxic to intact cells by strongly and instantly active in lysed cells. The binding of the whole toxin through the B subunit Is followed by a lag before subunit A penetrates the cell membrane.
• Describe the action of the cholera toxin inside mucosal cells

  1. Cholera toxin is endocytosed and fuses with the ER, so the B subunits are bound to the ER membrane.
  2. Disulphide isomerase cleaves CT to release the A1 subunit, which is secreted out of the ER via Sec61.
  3. A1 subunit reforms its shape and locks adenylate cyclase into an on position, so that there is constant production of cAMP, which impacts chloride channels and leads to loss of Cl-.
• How does cholera toxin lock adenylate cyclase is an active form?

  CT targets the inhibitory G protein by taking the ADP ribosyl group from NAD and attaches to the G protein. This prevents inhibitory G protein from inactivating it. Leads to dramatic increase in cAMP.
• Describe the pathogenesis of cholera

  1. V. Cholerae ingested an ph shock in stomach and increased temperature trigger the expression of virulence genes.
  2. It then adheres to and colonises the small intestinal mucosa.
  3. Begins to produce and secrete cholera toxin, which acts on mucosal cells to alter their function so that they drive the movement of water and ions out of the tissue.
  4. This results in extensive fluid and ion loss from tissues leading to hypotension, electrolyte imbalance and death.