Bacterial Pathogens And Disease 2

Question 1

What is a endotoxin?

Answer 1

the main component of the outer membrane of the cell wall of Gram-negative bacteria.

Question 2

What structures are present in the gram negative bacterial cell wall?

Answer 2

Proteins and porin and liposacharride - outer membrane

Lipoprotein

Peptidoglycan

Question 3

What is the structure of the liposacharride?

Answer 3

Lipid A - associates with membrane

Core polysaccharide

O side chain

Question 4

Describe the lipid A subsection of a liposacharride?

Answer 4

• phosphorylated glucosamines attached to long chain fatty acids
• number and type of fatty acid vary by species
• hydrophobic

Question 5

Describe the polysaccharide core of the lipopolysachrride

Answer 5

KDO and heptose

Relatively constant between species

Hydrophilic

Question 6

Describe the O side chain of lipopolysacharride

Answer 6

• Repeat units of tri, tetra, or Penta saccharide sugars
• highly variable between species
• hydrophilic

Question 7

What are the characteristics of endotoxin?

Answer 7

• Endotoxin is lipopolysaccharide (LPS)
  • Lipid A is the active component. – not immunogenic.
  • O antigen is highly immunogenic and immune specific.
  • Found only in gram negative bacteria.
  • Heat stable
  • Not converted to toxoids.
  • Major initiator of the sepsis pathway.

Question 8

What is sepsis?

Answer 8

Life threatening organ dysfunction caused by a dysregulated host response to infection

Question 9

What innate immune system cells primarily drive sepsis?

Answer 9

•macrophages,
•monocytes,
•granulocytes,
•natural killer cells
•dendritic cells.

Question 10

What do the innate immune cells detect in sepsis?

Answer 10

•pathogen associated molecular patterns (PAMP’s) such as endotoxin,
•damage associated molecular patterns (DAMP’s) from damaged host cells.

Question 11

What is the detection of innate immune cells mediated by?

Answer 11

•cell membrane receptors
– toll-like receptors (TLR) and C-type lectin receptors.
•cytosol receptors
- NOD-like receptors, RIG-I-like receptors.

Question 12

What is the effect of detection in sepsis?

Answer 12

•Production of pro-inflammatory cytokines TNFα, IL-1, IL-6
•via inflammasomes to produce IL-1β and IL-18 that cause rapid programmed cell death

Question 13

Describe the signalling pathways of LPS

Answer 13

1. LPS binds to MD2 and CD14 on the cel surface of a host
2. This causes a cascade inside the cell causing mydosome formation
3. TRAF6 forms
4. Activation of NF-kb by TRAF6
5. This causes production of TNF-alpha and other cytokines

Question 14

Why are pro inflammatory cytokines important

Answer 14

• 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

Question 15

What are the positive and negatives of dis regulation of sepsis?

Answer 15

Achieves rapid control of localised and minor infections

However, process may pass a threshold - systemic injury

Question 16

What occurs during dysregulation of sepsis?

Answer 16

Production of reactive oxygen species (ROS) - damages cellular proteins, DNA and lipids + impared mitochondri

Complement activation —. Increase ROS, granulocyte enzyme release, endothelial permeability and tissue factor expression

Widespread immunothrobsis - disseminated intravascular coagulation (DIC) + impaired micro vascular function + organ dysfunction

Mitochondrial damage leads to decreased intracellular TP an cells enter sate of hibernation - exacerbates organ dysfunction

Question 17

What is the resolution of sepsis?

Question 18

What is Meningococcal Sepsis?

Answer 18

• Caused by Neisseria meningitidis
• Gram negative diplococcus
• Serotypes A,B,C, Y, W135
• Serotype A associated with large outbreaks in Sahel region of Africa – Meningitis belt.
• Serotype B,C and W135 found in UK – declined since introduction of MenC and now MenB vaccine.

Question 19

What makes meningococcus so effective in sepsis?

Answer 19

It’s a active endotoxin and can go anywhere away from bacteria

Question 20

What do pro flammitory cytokines cause?

Answer 20

Cause fever.
• Causes neutrophils to release extra-cellular traps (NETs) made of DNA and antimicrobial proteins that forms a scaffold for platelet activation.
• Cause release of microparticles by activated platelets
• Increase tissue factor expression by blood monocytes