Bacterial pathogens and disease - endotoxins

Question 1

What are endotoxins?

Answer 1

= is a component of the exterior cell wall of Gram-negative bacteria and is a lipopolysaccharide (LPS)

Question 2

What the 3 parts to the endotoxin?

Answer 2

LPS is made up of:

• O side chain
  
  • repeat units of sugar
  • hydrophilic
  • variable between species
  • highly immunogenic and immune specific
• Polysaccharide core
  
  • constant between species
  • hydrophilic
• Lipid A
  
  • Very long and specific fatty acid chains
  • hydrophobic
  • active component - not immunogenic

Question 3

What are the characteristics of endotoxins?

Answer 3

Heat stable

Not converted to toxoids

Major initiator of the sepsis pathway

Question 4

Describe sepsis and how it works

Answer 4

= life threatening organ dysfunction caused by a dysregulated host response to infection

• driven by the innate immune system (macrophages, NK cells)
• The cells within the system will detect PAMPs and DAMPs (damaged equivalent of PAMPs from damaged host cells)
  
  • detected by cell membrane receptors (toll-like) and cytosol receptors
• As a result, pro-inflammatory cytokines are produced - IL-1,IL-6, IL-18
  
  • causing cell death

Question 5

What are the effects of pro-inflammatory cytokines?

Answer 5

• Increase number, lifespan and activation state of innate immune cells
• Increase adhesion molecule and chemokine expression by endothelial cells
• Increase acute phase protein such as complement, fibrinogen and CRP
• Cause fever
• Causes neutrophils to release extra-cellular traps made up of DNA that forms a scaffold for platelet activation
• Cause release of microparticles by activated platelets
• Increase tissue factor expression by blood monocytes
• –> causes formation of thrombus

Question 6

What is the dysregulation immune response?

Answer 6

The process of sepsis achieves a rapid control of localised and minor infections

However if the process passes a threshold –> system injury:

• Production of reactive oxygen species (ROS) which damages cellular proteins, DNA and lipids and impairs mitochondria
• Complement activation - increase ROS, granulocyte enzyme release
• Widespread immunothrombosis leading to DIC with impaired microvasculature function
• Mitochondrial damage leads to decrease ATP and cells enter state of hibernation and organ damage - irreversible state of organ damage

Question 7

What is the resolution of sepsis?

Answer 7

• Anti-inflammatory - IL-10 produced
  
  • suppresses IL-6 production
• Autophagy of PAMPs and DAMPs - removal
• Damaged cells undergo apoptosis and engulfment

Question 8

What is a key factor that triggers sepsis?

Answer 8

The production of highly reactive or large amounts of polysaccharides

Eg.: Meningococcal Sepsis

• Gram negative diplococcus
• Can cause diseases ranging from meningitis to life threatening meningococcal sepsis