Bacterial Pathogens and Disease II - Endotoxins Flashcards
What is the difference in the peptidoglycan layer in gram + and - bacteria?
β gram - have very thin peptidoglycan cell walls compared to gram +
What are the three components of lipopolysaccharide?
β Lipid A
β polysaccharide core
β O- side chain
What is Lipid A made from?
β Phosphorylated glucosamines attached to long chain fatty acids and is hydrophobic
What is the polysaccharide core made from?
β Ketodeoxyoctanoid acid (KDO) and heptose
β relatively constant between species - hydrophilic
What is the O side chain made from?
β Repeat units of tri tetra or pentasaccharide sugars
β hydrophilic
What is endotoxin?
β lipopolysaccharide
What is the active component of endotoxin?
β Lipid A is the active component that is not immunogenic
Why does a vaccine for all O antigens not work?
β each type of O antigen elicits a specific response
What 3 things are in the membrane of gram -ve bacteria?
β Proteins
β Porins
β lipopolysaccharide
What is a major initiator of the sepsis pathway?
β lipopolysaccharide
What is a structural property of lipopolysaccharide?
β Heat stable
Why canβt you make a vaccine against lipid A?
β not immunogenic
What is the definition of sepsis?
β Life threatening organ dysfunction caused by dysregulated host response to infection
What 5 components of the immune system drive the sepsis response?
β Macrophages β monocytes β granulocytes β natural killer cells β dendritic cells
What does the immune system detect during sepsis?
β Pathogen associated molecular patterns (PAMPs) such as endotoxins
β damage associated molecular patterns (DAMPs) from damaged host cells
What two categories of receptor are used to detect PAMPs and DAMPs?
β Cell membrane receptors and cytosol receptors
Give 2 examples of cell membrane receptors that are used to detect PAMPs and DAMPs?
β Toll like receptors
βC-type lectin receptors
Give 2 examples of cytosol receptors used to detect PAMPs and DAMPs?
β NOD-like receptors
β RIG-I like receptors
What is the effect of detecting PAMPs and DAMPs and how is this mediated?
β Production of pro-inflammatory cytokines : TNFa, IL-1, IL-6
β via inflammasomes to produce IL-1beta and IL-18 that cause rapid programmed cell death
Describe how cytokines are produced as a result of LPS binding?
β LPS binds to a macrophage (CD14 receptor)
β after it is bound by CD14 it gets passed to the toll-like receptor (TLR4) by MD2
β The TLR4 dimerizes
β causes myddosome formation intracellularly
β Activation of NF-Kb
β Production of TNF alpha and other cytokines occur
What are the 7 effects of pro-inflammatory cytokines?
1) increase number,lifespan and activation state of innate immune cells
2) increase adhesion molecule and chemokines expression by endothelial cells
3) increases acute phase protein such as complement , fibrinogen and CRP
4) cause fever
5) causes neutrophils to release extracellular traps (NETs) made of DNA and antimicrobial proteins that form a scaffold for platelet activation
6) cause release of microparticles by activated platelets
7) increase tissue factor expression by blood monocytes
What 3 things lead to the formation of an immunothrombosis?
β neutrophils releasing NETs
β microparticles released by activated platelets
β tissue factor expression increase by blood monocytes
What is the reason for the pro-inflammatory cytokine effects?
β Rapid control of localised and minor infections
What is the effect of TNF in the liver and why?
β cause a decrease in iron
β liver tries to collate the iron because bacteria need it to grow
What is septicaemia driven by?
β Endotoxin
What are 5 things that occur during sepsis?
β increased vascular permeability β hypotension leading to hypovolaemic shock β fever β DIC β multiple organ failure
What are 4 things that occur as a result of dysregulation?
β production of reactive oxygen species
β complement activation
β Widspread immunothrombosis leading to DIC
β Mitochondrial damage
What are two reactive oxygen species?
β Hydroxyl and nitric oxide
What is the function of reactive oxygen species?
β damages cellular proteins
β Damages DNA and lipids
β impairs mitochondria
What happens during complement activation?
β granulocyte enzyme release
β endothelial permeability
β tissue factor expression
β C5a increase ROS
What is DIC?
β clots are formed everywhere but they start bleeding because all the clotting factors are used up
What does mitochondrial damage lead to?
β decreased intracellular ATP
β cells enter a state of hibernation and exacerbates organ dysfunction
What kind of a process is sepsis resolution?
β Active not passive
What are the three things that occur in the resolution of sepsis?
β Anti-inflammatory IL-10 is produced early in the process
β Autophagy of PAMPs and DAMPs
β Damaged cells undergo apoptosis and engulfment by macrophages
What is the effect of IL-10 being produced during sepsis resolution?
β Suppresses production of IL-6 and gamma interferon
β Stimulates the production of a soluble TNF receptor and IL-1 receptor antagonist
Why are there TNF receptors in the blood in sepsis resolution?
β TNF binds to the receptor instead of being taken up by cells
What is the function of IL-1 antagonist in sepsis resolution?
β IL-1 antagonist competes for binding so less IL-1 can bind to the receptor
What types of cytokines are IL-6 and gamma interferon?
β Pro inflammatory
What bacteria is meningococcal sepsis caused by?
β Neisseria meningitidis
What kind of bacteria is neisseria meningitidis?
β Gram negative diplococcus
What are the 5 serotypes of meningococcal sepsis?
β A β B β C β Y β W135
What serotype is associated with outbreaks in the Sahel region of Africa?
β A
What serotypes of meningitidis are found in the UK?
β B
β C
β W135
What are the 5 things that make meningococcus so effective in sepsis?
β It has a different lipid A and polysaccharide to all gram -ve bacteria
β 6 fatty acid chains
β Similar carbohydrates to the ones in humans so the immune response is not very effective
β blebs are pieces of outer cell membrane which are shedded all the time - shedding endotoxins into the environment
