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M&I: Pathogens & Pathogenesis > Bacterial Pathogens And Disease 2- Endotoxins > Flashcards

Bacterial Pathogens And Disease 2- Endotoxins Flashcards

1
Q

What is an endotoxin?

A

A component of the gram negative cell wall - is an essential component of it that also causes disease

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2
Q

Name the 3 components of lipopolysaccharide (LPS)

A
  • O side chain (O polysaccharide)
  • Core polysaccharide
  • Lipid A
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3
Q

What are the components of a gram negative bacterial cell wall?

A

Lipopolysaccharide
Peptidoglycan
Cell membrane

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4
Q

What are the features of the O-polysaccharide?

A

Highly variable between species
Hydrophilic

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5
Q

What are the features of a core polysaccharide?

A

Relatively constant between species and hydrophilic

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6
Q

What is a core polysaccharide made up of?

A

Ketodeoxyctenoic acid and heptose

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7
Q

What is an O-polysaccharide made up of?

A

Repeat units of tri-, tetra- or pentosaccharide sugars

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8
Q

What is lipid A made up of?

A
  • phosphorylated glucosamines attached to very long fatty acids
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9
Q

What are the features of lipid A?

A
  • Number and type of fatty acid varies by species
  • Hydrophobic
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10
Q

Is Lipid A (part of LPS) immunogenic?

A

Not immunogenic but is an active component

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11
Q

Is the O antigen side chain of LPS immunogenic?

A

Highly immunogenic and immune specific

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12
Q

Is LPS heat stable? Can it be converted to toxoids?

A

Endotoxin = LPS

  • Only in gram negative
  • Heat stable
  • Not converted to toxoids
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13
Q

What role does LPS have in sepsis?

A

Major initiator of sepsis pathway

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14
Q

Define sepsis

A

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

  • primarily driven by the innate immune system so by resident macrophages or WBCs that are easily recruited
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15
Q

Describe the general mechanism of sepsis/detection from endotoxin

A
  • WBC innate cells detect PAMPs such as endotoxin as well as DAMPs on host cells (cell damage)
  • This detection is mediated by toll-like receptors (TLR) and C-type lectin receptors (and cytosol receptors - NOD and RIG-I like receptors)
  • Causes the production of pro-inflammatory cytokines and inflammasomes produce IL-1 beta and IL18 that cause rapid programmed cell death
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16
Q

Explain how endotoxin or exotoxins can cause an overactive immune response that is inappropriate, leading to sepsis

A
  • We know the general mechanism of innate immunity and how this leads to production of cytokines but when the system is way too much cytokines produced = sepsis.
  • This happen as:

The bacteria will produce a normal, proportional immune response, but the presence of endotoxin or and exotoxin (acting as a superantigen) can cause an overactive, disproportional immune response = sepsis

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17
Q

Which TLR in particular binds endotoxin?

A

TLR4

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18
Q

What are Toll like receptors (TLRs)?

A

I believe that these are a type of PRR found on phagocytes that are specific to PAMPs, not specific antigens like in the adaptive IS so NOT TCRs

  • There are also other receptors that detect pathogens such as NOD like and RIG-I like receptors - do not know much about these
  • do not know if they also detect DAMPS
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19
Q

Explain what is happening in the image below - what is the function of the Myd88 pathway?

A

The fatty acid chains (lipid A) in endotoxin are detected by CD14 and then transferred from CD14 to TLR4 thanks to MD-2 (a globular protein)

  • TLR4 dimerises = signalling pathway (called Myd88 pathway)
  • signalling pathway causes NF-kB to translocate to nucleus to cause transcription of cytokines

→ so this is the mechanism of how immune cells bind to LPS endotoxin and therefore increase cytokine production in response

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20
Q

Which are the main cytokines produced in the immune response to LPS?

A
  • TNF-alpha
  • IL-1beta
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21
Q

Describe the different effects of pro-inflammatory cytokines on WBCs, endothelium and systemic effects

A
  • increase number, lifespan and function of WBCs
  • increase adhesion molecule and chemokine expression on endothelial cells
  • increase acute phase protein such as complement, fibrinogen and CRP
  • cause fever (pyrogens)
  • causes neutrophils to release extra-cellular traps (NETs) made of DNA and antimicrobial proteins - causes platelet activation
  • causes release of microparticles by activated platelets
  • increased tissue factor expression by monocytes
  • immunothrombis
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22
Q

Explain why we can have a dysregulated immune response (sepsis)

A

Sepsis occurs when the activating mechanisms are so much that the immune response is no longer regulated

23
Q

What is meant by disseminated intravascular coagulation (DIC) in sepsis?

A

This is due to widespread immunothrombosis leading to DIC causing impaired microvasculature so organ dysfunction

24
Q

How is complement affected in sepsis and what does this cause?

A

Activated - this increases ROS also, as well as granulocyte enzyme release, endothelial permeability and tissue factor expression

25
Q

How are mitochondria affected in sepsis?

A

Mitochondrial damage (by ROS?) causes decreased ATP and cells enter a state of hibernation → organ damage also

26
Q

How does sepsis cause cellular damage?

A
  • Production of reactive oxygen species (ROS) - Hydroxyl and nitric oxide - damages cellular proteins, DNA and lipids and impairs mitochondria.
  • Complement activation (esp. C5a) - increase ROS, granulocyte enzyme release, endothelial permeability and tissue factor expression.
  • Widespread immunothrombosis leading to disseminated intravascular coagulation (DIC) with impaired microvasculature function and organ
    dysfunction.
  • Mitochondrial damage leads to decreased intracellular ATP and cells enter state of hibernation - exacerbates organ dysfunction.
27
Q

Name some ways that the body tries to resolve sepsis

A
  • Anti-inflammatory IL-10 is produced early in process
  • Autophagy of PAMPs and DAMPs to remove them
  • Damaged cells undergo apoptosis
28
Q

Name 2 ways that IL-10 produces its anti-inflammatory effect?

A

Anti-inflammatory

  • suppresses production of IL-6 and gamma interferon
  • stimulates production of soluble TNF receptor and IL-1 receptor antagonist
29
Q

Name a cause of meningococcal sepsis

A

Neisseria meningtitidis

30
Q

Where is the bacteria (cause of meningococcal sepsis) found and what type of bacteria is this?

A

Large outbreaks in Sahel region of Africa - in the meningitis belt

31
Q

Describe how Neisseria meningtitidis causes sepsis so effectively

A

This bacteria has evolved to form a very reactive, shorter form of LPS that is actually released from the membrane in the form of blebs (protrusions of the membrane that are full of LPS)

  • can cause meningitis and life threatening meningococcal sepsis
32
Q

How does endotoxin cause DIC (disseminated intravascular coagulation)?

A

LPS (endotoxin) can activate Tissue factor (AKA factor 3) which will cause activation of the clotting cascade!

33
Q

What are lipoproteins made up of?

A
  • Porin
  • Protein
34
Q

What is peptidoglycan made up of?

A
  • Periplasm
35
Q

What is the cell membrane made up of?

A
  • Phospholipid
  • Proteins
36
Q

What are the features of an endotoxin?

A
  • Heat stable
  • Not converted to toxoids
37
Q

What are endotoxins a major initiator of?

A

The sepsis pathway

38
Q

What are the only types of bacteria endotoxins are found in?

A
  • Gram negatve bacteria
39
Q

Which is the active component of endotoxin?

A

Lipid A

40
Q

What is sepsis primarily driven by?

A

Innate immune system response

41
Q

What cells does the innate immune response involve?

A

Macrophages
Monocytes
Granulocytes
Natural killer cells
Dendritic cells

42
Q

What do the innate immune system cells detect?

A

PAMPs and DAMPs

43
Q

What is an example of a PAMP?

A

Endotoxin

44
Q

Where do DAMPs come from?

A

Damaged host cells

45
Q

What is PAMP and DAMP detection mediated by in sepsis?

A

Cell membrane receptors: TLR and C-type lectin receptors
Cytosol receptors: NOD and RIG-I-like receptors

46
Q

What are the effects of PAMPs and DAMPs in sepsis?

A

Production of pro-inflammatory cytokines TNFalpha, IL-1 and IL-6

47
Q

What are the effects of pro-inflammatory cytokines?

A

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 NETS
Release of microparticles by activated platelets
Increase tissue factor expression by blood monocytes

48
Q

What are NETs?

A

Neutrophil extracellular traps

49
Q

What are NETs made of?

A

DNA and antimicrobial proteins

50
Q

What do NETs form?

A

A scaffold for platelet activation

51
Q

What does the production of reactive oxygen species cause?

A
  • Damages cellular proteins, DNA and lipids
  • impairs mitochondria
52
Q

What are the meningococcal sepsis serotypes?

A

A, B, C, Y, W, 135

53
Q

What is serotype A associated with?

A

Large outbreaks in the Sahel region of africa

54
Q

How is meningococcal sepsis so effective?

A

Releases blebs full of LPS

M&I: Pathogens & Pathogenesis (7 decks)

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