Introduction to toxins

• Outline non-protein toxins

  • Endotoxins: embedded within the cell membrane, e.g., LPS
  • Other bacterial cell wall components, e.g., lipoteichoic acid
  • Mycolactone: produced by some mycobacteria and is responsible for Buruli ulcer
• Outline the difference between endotoxins and exotoxins

  Endotoxins:

  • LPS specific
  • Part of the outer membrane
  • Relatively low potency and low specificity

  Exotoxins:

  • Proteins
  • Secreted from the cell
  • Relatively high potency and high specificity
• Outline the 5 cardinal signs of inflammation

  1. Heat: results from increased blood flow due to vasodilation
  2. Redness: due to increased blood flow
  3. Swelling: due to increased vascular permeability leading to build up of fluids in the tissues
  4. Pain: due to pressure on nerve endings
  5. Loss of function: this can occur due to dysregulation of the immune system
• Describe how septic shock develops (4 stages)

  1. Systemic inflammatory response syndrome (SIRS), characterised by: abnormal temperature (above 38 or below 36), high respiratory rate, high neutrophil count and mild hypotension.
  2. Sepsis: SIRS with proof of bacteria in bloodstream
  3. Severe sepsis: multiple organ dysfunction and dramatic hypotension.
  4. Septic shock: disseminated intravascular administration (clots appear as a rash on the skin), acute respiratory distress and multiple organ failure and death.
• Describe the role of LPS in septic shock

  Bacterial lysis leads to release of LPS, which bind to LPS-binding protein, which in turn binds to CD14 with TLR4 on macrophages. This results in production of cytokines, such as TNF-alpha, IL-1, IL-6, IL-8 and platelet activating factor. This results in activation of the coagulation cascade and complement cascade. This results in release of prostaglandins and leukotrienes, which cause endothelial damage.
• Describe the cause of symptoms of septic shock

  • Activation of complement cascade leads to vasodilation and leakage of fluid into tissues, which leads to hypotension.
  • Cytokine release results in increased neutrophils, which damage vessels walls
  • Active coagulation cascade produces small clots that result in disseminated intramuscular coagulation.
• Describe the 3 different types of exotoxin

  Type I: superantigens

  • bind to host cell surface, but are not translocated into the cell. This results in antigen-dependent activation of T cells.

  Type II: pore-forming phospholipases

  • destroy cytoplasmic membrane integrity

  Type III: AB toxins

  • enzymatic A portion acts on intracellular host protein
  • B portion contains translocation domain and receptor binding domain
• Describe type I exotoxins

  These are known as superantigens as they bind indiscriminately to MHC class II molecules on T helper cells. This results in:

  • T cell activation
  • Massive release of non-specific cytokines, such as IL-2, which stimulates TNF-alpha and T cell proliferation.
  • Induces systemic inflammatory response

  CD4+ T cells can be linked by superantigens.
• List some examples of superantigens (Type I)

  Toxic shock syndrome toxin-1 (TSST-1):

  • produced by some strains of Staphylococcus aureus
  • causes toxic shock syndrome by inducing IL-2 release

  Staphylococcal enterotoxins (SEs):

  • produced by some strains of Staphylococcus aureus
  • interacts with vagus nerve in the stomach and leads to projectile vomiting

  Streptococcal pyrogenic exotoxin (Spe):

  • produced by group A streptococci
  • causes toxic shock like syndrome
• Describe type II exotoxins

  There are two main types:

  • Pore forming toxins: insert into host cell membrane and form pores, leading to ion imbalance. These toxins usually associate with cholesterol in the host cell membrane, which is not present in bacterial membrane.
  • Phospholipases: cleave the head from the phospholipids, which disrupts the membrane and causes damage.
• Describe some examples of type II exotoxins

  Pore forming toxins:

  • Staphylococcus alpha toxin is a pore forming cytolysin produced by S. aureus.
  • Listeriolysin O is a pore forming toxin that mediates escape from the phagosome. It is activated at low pH and produced by Listeria monocytogenes.
  • Pneumolysin is a pore forming cytolysin produced by Streptococcus pneumoniae. This toxin induces lung inflammation

  Phospholipases:

  • Clostridium perfingens alpha toxin causes gas gangrene