L2: Bacterial pathogens & disease- ENDOTOXINS Flashcards

1
Q

What are LPS detected by?

A

→ TLRs

→ innate immune response

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2
Q

What are LPS?

A

→ major outer surface membrane components present in almost all Gram-negative bacteria

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3
Q

Name the components of gram negative bacterial cell wall

A
→ lipopolysaccharide
→ outer membrane
→ lipoprotein
→ peptidoglycan
→ cell membrane
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4
Q

Describe the structure of LPS

A

→ LIPID A
→ POLYSACCHARIDE CORE
→ O – SIDE CHAIN

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5
Q

What is lipid A in LPS?

A

→ Phosphorylated glucosamines attached to long chain fatty acids.

→ Number and type of fatty acid vary by species.

→ Hydrophobic

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6
Q

Describe the polysaccharide core of LPS

A

→Ketodeoxyoctanoic acid (KDO) and heptose.

→ Relatively constant between species

→ Hydrophilic

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7
Q

Describe the O-side chain of LPS

A

→ Repeat units of tri, tetra or penta-saccharide sugars.

→ Highly variable between species

→ Hydrophilic

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8
Q

What is the active component of LPS?

A

→ Lipid A

→ not immunogenic

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9
Q

What is the immunogenic component of LPS?

A

→ O-antigen

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10
Q

What is the major initiator of sepsis pathway?

A

→ LPS

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11
Q

Describe endotoxins

A

→ Heat stable

→ Not converted to toxoids.

→ Major initiator of the sepsis pathway

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12
Q

How are LPS molecules cross bridged and what does this allow?

A

→ non covalently cross bridged by Ca and Magnesium ions

→ barrier to hydrophobic molecules including bile salts

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13
Q

What is sepsis?

A

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

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14
Q

What are the immune cells involved in sepsis?

A
→ macrophages,
→ monocytes, 
→ granulocytes, 
→ natural killer cells 
→ dendritic cells
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15
Q

What do innate immune 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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16
Q

How are DAMPs and PAMPs detected?

A

→ cell membrane receptors – toll-like receptors (TLR) and C-type lectin receptors

→ cytosol receptors - NOD-like receptors, RIG-I-like receptors

17
Q

What are the two types of detectors of DAMPs and PAMPs?

A

→ cell membrane receptors

→ cytosol receptors

18
Q

What are the effects of detection of PAMPs and DAMPs?

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

19
Q

After translocation to the nucleus, what is transcribed?

A

→ transcription of NF-kB

20
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

21
Q

What are the effects of pro-inflammatory cytokines on neutrophils?

A

→ release extra-cellular traps (NETs)
→ release granules with antimicrobial activity
→ Cause release of microparticles by activated platelets

→ Increase tissue factor expression by blood monocytes

22
Q

What are the functions of NETS?

A

→ proteins eg. histones that form a scaffold for platelet activation

23
Q

What do microbes trapped in NETS do?

A

→ attracts and activate further leucocytes

24
Q

What is produced in sepsis?

A

→ reactive oxygen species (ROS)
→ Hydroxyl and nitric oxide
→ Complements- 5a especially

25
Q

What causes cells to hibernate in sepsis?

A

→ Mitochondrial damage

→ decreased intracellular ATP

26
Q

What does widespread immunothrombosis lead to?

A

→ disseminated intravascular coagulation (DIC)

27
Q

What does activation of complements lead to?

A

→ granulocyte enzyme release,

→ endothelial permeability
→ tissue factor expression

28
Q

How is sepsis resolved?

A

→ Anti-inflammatory
IL-10 produced early in process
→ Autophagy of PAMP’s and DAMP’s
→ damaged cells undergo apoptosis

29
Q

What do anti-inflammatories do in sepsis?

A

→ Supresses production IL-6 and γ-interferon

→ Stimulates production of soluble TNF receptor and IL-1 receptor antagonist

30
Q

What is Meningococcal Sepsis caused by?

A

→ Neisseria meningitidis

→ Gram negative diplococcus

31
Q

What are the serotypes of Meningococcal sepsis?

A

→ A,B,C, Y, W135

32
Q

What is the difference in serotype A and B of meningococcal sepsis?

A

→ Serotype A associated with large outbreaks in Sahel region of Africa – Meningitis belt

→ Serotype B,C and W135 found in UK

33
Q

What makes meningococcus so effective?

A

→ very active LPS
→ released from blebs
→lacks o-antigen

34
Q

What are the symptoms of MS?

A

→ oedema
→ fever
→ dark purple rash
→ organ failure