Bacterial Pathogens and Disease II- Endotoxins Flashcards

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1
Q

Describe Gram negative bacterial cell wall

A
  • Peptidoglycan layer on top of cell membrane
  • Lipopolysaccharides present on the outside of the cell wall
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2
Q

Describe the structure of a lipopolysaccharide

A

LIPID A:

  • Phosphorylated glucosamines attached to long-chain fatty acids
  • Number and type of fatty acid vary by species
  • Hydrophobic

POLYSACCHARIDE CORE:

  • Ketodeoxyoctanoic acid (KDO) and heptose
  • Relatively constant between species
  • Hydrophilic

O – SIDE CHAIN:

  • Repeat units of tri, tetra or penta-saccharide sugars.
  • Highly variable between species
  • Hydrophilic
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3
Q

What are the characteristics of endotoxins

A
  • 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.
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4
Q

What is sepsis

A

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

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5
Q

What cells are involved in sepsis

A
  • macrophages
  • monocytes
  • granulocytes
  • natural killer cells
  • dendritic cell
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6
Q

What do these cells detect

A
  • pathogen associated
    molecular patterns
    (PAMP’s) such as
    endotoxin,
  • damage associated
    molecular patterns
    (DAMP’s) from
    damaged host cells.
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7
Q

What is this detection mediated by

A
  • cell membrane
    receptors – toll-like
    receptors (TLR) and C
    -type lectin receptors.
  • cytosol receptors -
    NOD-like receptors,
    RIG-I-like receptors
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8
Q

What is the effect of these cells

A
  • 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
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9
Q

What are the effects of pro-inflammatory cytokines

A
  • Increase the 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
    (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
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10
Q

What is meant by the dysregulation of sepsis

A

The process described achieves rapid control of localised and minor infections
- However, the process may pass a threshold → systemic injury

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11
Q

Describe the 4 pathways of the dysregulation of sepsis

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.
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12
Q

How is sepsis resolved

A

Active process - not passive

Anti-inflammatory
IL-10 produced early in process:

  • Supresses production
    IL-6 and y-interferon
  • Stimulates production of soluble TNF receptor and IL-1 receptor antagonist

Autophagy of PAMP’s and DAMP’s - removal

Damaged cells - undergo apoptosis and engulfment by macrophages

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13
Q

What is meningococcal sepsis

A
  • 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.
  • Can cause disease ranging from meningitis to life threatening meningococcal sepsis.
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14
Q

What makes meningococcus so effective in sepsis?

A
  • LOS is shorter and lacks the O-antigen
  • causes belting of the bacteria
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