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Core Concepts in Immunology > Lecture 26: TLRs > Flashcards

Lecture 26: TLRs Flashcards

1
Q

What is TL4 ?

A

LPS sensor

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2
Q

What is the C3H/HeJ mouse ?

A

Mutation inTIR domain of TLR4 that converts a conserved proline resiue to a histidine mice resistant to LPS lethality

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3
Q

What is the TIR domain made up of ?

A
  1. 3 boxes of conserved residues set in core sequence of 130-160 aa with intervening variable residues
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4
Q

What is the structure of TIR domain ?

A

Central 5-stranded parallel B-sheet surrounded by 5-helices on each side

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5
Q

What is the only TLR that heterodimerises ?

A

TLR2

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6
Q

What can TLR2 heterodimerise with ?

A

TLR1 and TLR6

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7
Q

What does TLR1 and TLR2 sense ?

A

Triacyl lipopeptides

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8
Q

What does TLR2 and TLR6 sense ?

A

Diaceylated lipopeptides

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9
Q

What does TLR5 sense ?

A

Flagellin

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10
Q

What does TLR4 sense ?

A

LPS

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11
Q

What does TLR3 sense ?

A

Double stranded RNA

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12
Q

What does TLR7 sense ?

A

Single stranded RNA

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13
Q

What does TLR8 sense ?

A

Single stranded RNA

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14
Q

What does TLR9 sense ?

A

CpG DNA

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15
Q

How does sensing of TLRs occur ?

A

Binding of ligand to ligand recognition receptor drivers dimerisation of partner TLRs

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16
Q

What is the response of TLR signalling ?

A

Dimerisation of receptors brings TIR domains together. Adapter proteins are then recruited

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17
Q

What does MyD88 do ?

A

Initiates signalling to NFkappaB

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18
Q

What does TRIF do ?

A

Initiates signalling to IRFs

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19
Q

What is the bridge MyD88 uses ?

A

Mal bridge

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20
Q

What is the bridge TRIF uses ?

A

TRAM

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21
Q

What is the accessory protein of TLR4 ?

A

MD2

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22
Q

What does the MD2-LPS interaction trigger ?

A

TLR4 homodimers

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23
Q

How does TLR4 initiate TIR signalling ?

A

Intracellularly

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24
Q

In TLR2 what does direct interactions with lipopeptide ligand drive ?

A

Heterodimerisation

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25
Q

What does TLR2 use for signalling ?

A

Mal - MyD88/NFkappaB

26
Q

Why does MAL sensitise ?

A

For optimal NFkappaB

27
Q

Where is TLR3 found ?

A

On endosomal membrane

28
Q

What does TLR3 recruit ?

A

TRIF

29
Q

What does TRIF drive ?

A

Signalling to IRF3 via TRAF3

30
Q

What does TLR3-TRIF activate ?

A

NFkappaB

31
Q

What is the interaction between TLR4 and TLR3 ?

A

TLR4 translocates to endosomal membrane via TRAM to engage TRAF3

32
Q

Where is TLR9 found ?

A

Endosomal membrane

33
Q

What is TLR9 a sensor of ?

A

Unmethylated CpG- DNA

34
Q

What regulates the localisation of TLR9 ?

A

UNC93B

35
Q

What does TLR9 recruit ?

A

MYD88

36
Q

What do synthetic oligodeoxynucleotides do ?

A

Bind different sites increasing signal

37
Q

What is imiquiomod ?

A

Synthetic TLR7 agoinist - melanoma

38
Q

What does TLR5 trigger ?

A

MyD88

39
Q

What does TLR7 and 8 trigger ?

A

MyD88

40
Q

Where is TLR10 not functional ?

A

Mice

41
Q

What are the TLR effector functions ?

A
  1. MyD88/NFkappaB signalling
  2. TRIF/IRF signalling
  3. Activates MAP kinases
  4. Alter phagocytic capacity
    5.Maturation of cytokine
  5. Enhances expression of anti-microbial genes
42
Q

What do TLR4-MAL/TRAM sorting adapter do ?

A

Get the signal to where it needs to be to drive specific effects

43
Q

What do endosomal TLRs, chaperone proteins do ?

A

Get the receptor where it needs to be to encounter specific ligands

44
Q

What preferentially engages TRAM/TRIF internalisation pathways ?

A

Co- receptor CD14

45
Q

What helps the internalisation and delivery to endolysosome for TLR recognition uptake ?

A

Association of DNA with antibodies

46
Q

What are NOD like receptors ?

A

Cytosolic proteins

47
Q

What are NOD like receptors a sensor of ?

A

Breakdown products of PGN

48
Q

What does NOD1 recognise ?

A

DAP

49
Q

What does NOD2 recognise ?

A

MDP

50
Q

What is the structure of NOD like receptor ?

A
  1. Leucine rich repeats
  2. Nucleotide binding domain
  3. CARD
51
Q

What does the CARD-CARD interaction with RIP2 in NOD like receptors activate ?

A

NFkappaB and MAP-K

52
Q

What does maturation to bio-active IL-1B require ?

A

Intracellular proteolytic cleavage by caspase 1

53
Q

What are included in the families of inflammasomes ?

A
  1. NLRP1
  2. NLRP3
  3. NLRC4
  4. Caspase-11
  5. AIM 2
54
Q

What is AIM2 ?

A

Cytosolic DNA binding protein

55
Q

What does AIM2 have ?

A
  1. Hin domain
  2. PYD
56
Q

What does AIM2 recruit ?

A

ASC

57
Q

What is cGAS ?

A

Cytosolic enzyme

58
Q

What does cGAS do in the presence of dsDNA ?

A

Generate 2* messenger cGAMP

59
Q

What does cGAMP bind ?

A

STING on er

60
Q

What is the caveat of of cGAS ?

A

cGAS detects dsDNA but some microbial RNA can form DNA:RNA hybrids or be RT’d to generate dsNA intermediates sensed by cGAS -STING

Core Concepts in Immunology (22 decks)

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