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Medical Microbiology > Bacterial Pathogens and Diseases II (Endotoxins) > Flashcards

Bacterial Pathogens and Diseases II (Endotoxins) Flashcards

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Biology 101 flashcards USMLE® Step 1 flashcards
1
Q

Describe the membranous layers of bacteria

A

All bacteria have an inner membrane

Gram +ve have an outer peptidoglycan layer

Whereas Gram -ve have an extra outer membrane

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2
Q

Describe the structure of Gram -ve outer membrane

A

Outer membrane: bilayered, outer leaflet distinct in that it has lipopolysaccharide (endotoxin)

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3
Q

Where is gram-ve peptidoglycan layer situated?

A

Within periplasmic space, gram -ve have the peptidoglycan layer

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4
Q

What are the 3 components of lipopolysaccharides (LPS)?

A

Lipid A component
Polysaccharide Core
O-side Chain

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5
Q

Describe the lipid A component of LPS

A

Phosphorylated glucosamines attached to long chain fatty acids.

No. and type of fatty acid vary by species.

Hydrophobic

Main toxigenic component of endotoxin

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6
Q

Outline the structure of the polysaccharide core of LPS

A

Keto Deoxy Octanoic acid (KDO) and heptose

Relatively constant between species.
Hydrophilic

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7
Q

Describe the structure of the O-side chain

A

Repeat units of tri, tetra or pentasaccharide sugars.
Highly variable between species
Hydrophilic

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8
Q

How do LPS molecules protect against hydrophobic molecules?

A

LPS molecules non covalently cross bridged by Ca and Magnesium ions – provides a barrier to hydrophobic molecules including bile salts

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9
Q

Outline characteristics of endotoxins

A
  • Endotoxin is lipopolysaccharide (LPS)
  • Lipid A active component; not immunogenic
  • O antigen is highly immunogenic + immune specific
  • Only gram-ve bacteria
  • Heat stable
  • Not converted to toxoids
  • Major initiator of sepsis pathway
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10
Q

What is sepsis?

A

Life threatening organ dysfunction caused by dysregulated host response to infection by innate immunity

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11
Q

Which cells are active in sepsis?

A

Sepsis driven by innate immune response:

  • macrophages
  • monocytes
  • NK cells
  • Dendritic cells
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12
Q

How does the innate immune response initiate sepsis?

A

Receptors recognise bacterial components (PAMPs) and/or danger signals (DAMPs) to activate cytokine transcription that will then recruit an inflammatory response

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13
Q

What are PAMPs?

A

pathogen associated molecular patterns e.g. endotoxin

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14
Q

What are DAMPs?

A

damage associated molecular patterns from damaged host cells

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15
Q

How is DAMPs/PAMPs detection by innate immune cells mediated?

A

Cell membrane receptors
- toll-like receptors (TLR)

Cytosol receptors
- NOD-like and RIG-I like receptors

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16
Q

What is the effect of PAMPs/DAMPs recognition by immune cells?

A

Pro-inflammtory Cytokine production (TNF-a, IL-1, IL-6)

Inflammasomes induce IL-1b and IL-18 production
- causes rapid apoptosis

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17
Q

What are PRRs?

A

pattern recognition receptors

  • recognise PAMPs
    e. g. TLRs
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18
Q

Which TLR is commonly paired with sepsis?

A

TLR4 are the PRRs that pair mostly with sepsis LPS

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19
Q

Outline a similarity between endo- and exotoxins

A

Both endo- and exotoxins have the ability to produce proinflammatory cytokines either through lymphocytes (exotoxins) or lipopolysaccharides (endotoxins)

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20
Q

Outline how E.coli endotoxin activates TLR4

A
  1. Lipid A component of LPS is recognised by MD-2
  2. MD-2+LPS bind to TLR4 molecule on the cell surface
  3. Causes dimerization of TLR4 causing intracellular
    signalling
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21
Q

How does the TLR4 complex form when endotoxin binds?

A

MD2 has a coreceptor binding protein CD14 that enables the formation of the complex on TLR4

22
Q

What is the effect of TLR4 activation?

A

The binding to TLR4 causes activation of an intracellular cascade that eventually leads to NF-Kꞵ activation

23
Q

What is the significance of NF-Kꞵ activation?

A

NF-Kꞵ activation leads to production of proinflammatory cytokines

24
Q

What is the effect of cytokines on immune cells?

A

Increase number, lifespan and activation state of innate immune cells
Cause fever

25
Q

Describe how cytokines effect endothelial cells

A

Increase adhesion molecules and chemokine expression by endothelial cells

26
Q

What effect does cytokines have on acute phase proteins?

A

Increase acute phase protein such as complement , fibrinogen and CRP

27
Q

Outline the effects of cytokines that lead to a thrombus formation

A
  1. Causes neutrophils to release extracellular traps (NETs) made of DNA and antimicrobial proteins that form a scaffold for platelet activation.
  2. Cause release of microparticles by activated platelets
  3. Increase tissue factor expression by blood monocytes
28
Q

What is the purpose of thrmobus formation by cytokines?

A

Formation of a thrombus (immunothrombosis) traps microbes within this
Attracts and activates further leukocytes.

29
Q

How do we define all the cytokine actions occurring at once?

A

All these effects together are called septicemia or septic shock

30
Q

Why is there such a drastic immune response to LPS?

A

Very potent immune response even in presence of small amounts of LPS as gram -ve bacteria in the bloodstream is life threatening and can be lethal

31
Q

What are the common symptoms cuased by LPS?

A

LPS causes the following symptoms:

  • Iron deficiency
  • Fever
  • Hypoglycaemia
  • DIC Thrombosis
  • Hypotension
  • Shock
32
Q

What effect does LPS have on macrophage activity?

A

LPS activate macrophages to produce TNF (IL-1):

  • causes a fever
  • Decreases Fe; liver tries to collate Fe so bacteria can’t grow
  • Causes endothelial cells to express receptors
33
Q

How does LPS effect mast cells?

A

LPS causes mast cells to degranulate producing mediators

34
Q

How do LPS cause liver damage?

A

Endotoxins also lead to liver damage due to release of acute phase proteins reducing glucose levels

35
Q

What is the effect of LPS Platelet activation?

A

Also activates platelets causing:

Increased vascular permeability; neutrophil recruited to damage site are able to get into tissue; can cause low BP ⇒ shock

Disseminated intravascular coagulation (DIC) ⇒ thrombosis

36
Q

How does LPS lead to thrombosis?

A

Complement pathway can also be activated as well as clotting mechanisms ⇒ hypotension and thrombosis

37
Q

Outline the signs and symptoms of sepsis

A
  • Increased vascular permeability
  • Hypotension leading to hypovolemic shock
  • Fever
  • Disseminated intravascular coagulation (DIC)
  • Multiple organ failure
38
Q

What is bacteraemia?

A

Bacteria present in blood but have short lifespan due to phagocytosis

39
Q

What is septicaemia?

A

Long lasting harmful bacteria in blood unable to be phagocytosed by macrophages

Septic shock mortality: 50-85%

40
Q

What is the aim of sepsis dysregulation?

A

Achieves rapid control of localised and minor infections

41
Q

Why does sepsis dysregulation not always occur?

A

However dyregulation may pass threshold → systemic injury

Tissue factor; initiation of thrombin formation from prothrombin + clotting

Tissue factor pathway; extrinsic

42
Q

How does sepsis damage mitochondria?

A

Production of reactive oxygen species (ROS) – Hydroxyl and nitric oxide – damages cellular proteins, DNA and lipids and impairs mitochondria

43
Q

What are the consequences of complement pathway activation in sepsis?

A

Complement activation (esp. C5a) – increase ROS, granulocyte enzyme release, endothelial permeability and tissue factor expression

44
Q

How does sepsis lead to DIC thrombosis?

A

Widespread immune thrombosis leading to disseminated intravascular coagulation (DIC) with impaired microvascular function and organ dysfunction

45
Q

What is the consequence of mitochondrial damage in sepsis?

A

Mitochondrial damage leads to decreased intracellular ATP and cells enter a state of hibernation – exacerbates organ dysfunction

46
Q

How is sepsis mediated?

A

Sepsis is actively negatively regulated by anti-inflammatory cytokines e.g. IL-10

47
Q

What are the regulatory effects of IL-10 for sepsis?

A

suppresses proinflammatory cytokines; IL-6 and ɣ-interferon

Produces receptors for proinflammatory cytokines (TNF and IL-1) to bind and downregulate them - antagonis

48
Q

What causes meningococcal sepsis?

A

Caused by Neisseria meningitidis

Gram negative diplococcus

49
Q

What are the different types of meningococcal sepsis?

A

Serotypes A,B,C, Y, W135 - varying O side chains

50
Q

What is the effect of meningococcal sepsis?

A

Can cause disease ranging from meningitis to life threatening meningococcal sepsis.
> meningococcus is very effective in sepsis

Medical Microbiology (15 decks)

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