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Innate Immunity > TLRs > Flashcards

TLRs Flashcards

1
Q

What repeats do all TLRs possess?

A

Amino-terminal leucine rich repeats (LRR)

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2
Q

What are LRRs responsible for?

A

Recognition of P(M)AMPs

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3
Q

What is the carboxy-terminal of TLRs?

A

Toll-interleukin-1 receptor (TIR) domain

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4
Q

What is the TIR in TLRs for?

A

Initiating intracelllular signalling

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5
Q

How many TLRs in humans and mice?

A

10 in humans
12 in mice

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6
Q

What TLRs are conserved in humans and mice?

A

TLRs 1-9

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7
Q

What TLRs are not functional in mice?

A

TLR10

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8
Q

What TLRs do not occur in the human genome?

A

TLR11, 12 and 13

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9
Q

What TLR is the ligand unclear for?

A

TLR10

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10
Q

Which TLR only works as a heterodimer?

A

TLR2

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11
Q

What can TLR2 form heterodimers with?

A

TLR1 or 6

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12
Q

Which TLRs can form homodimers?

A

3, 4, 5, 7, 8, 9

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13
Q

Which TLR binds LPS?

A

TLR4

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14
Q

What can TLR1 and 2 bind to?

A

Triacyl lipopeptide

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15
Q

What specific pathogen can TLR2-6 recognise?

A

Mycobacteria

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16
Q

What is TLR2 normally recognising?

A

Gram positive bacteria
Fungi
Mycobacteria

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17
Q

What does TLR5 bind?

A

Flagellum

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18
Q

What does TLR3 bind?

A

DsRNA

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19
Q

What type of nucleic acid is bound by TLR7 and 8?

A

SsRNA

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20
Q

What nucleic acid is bound by TLR9?

A

DNA

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21
Q

What TLR only signals through myd88?

A

TLR5

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22
Q

What are the 3 regions of LPS?

A

O region
R region
Lipid A region

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23
Q

What is the O region of LPS?

A

Polysaccharide

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24
Q

What is the R region of LPS?

A

Core polysaccharide

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25
Q

What type of affinity does TLR4 have for LPS?

A

Low affinity - it requires other proteins to recognise LPS

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26
Q

What proteins does TLR4 require to recognise LPS?

A

LBP
CD14
MD2

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27
Q

What do MD2 and TLR4 do?

A

Form a heterodimer that represent functional LPS receptor

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28
Q

What does CD14 do?

A

Enhances the sensitivity to LPS

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29
Q

What do 5 of the 6 acyl chains of lipid A interact with?

A

A hydrophobic pocket present in MD2 within the TLR4-MD2 heterodimer

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30
Q

What does the sixth acyl chain of lipid A interact with?

A

With a different TLR4 molecule

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31
Q

Where does binding of TLR4 to MD-2 occur?

A

At the concave face of the TLR4 extracellular domain

32
Q

What receptors promote delivery of PAMPs to TLR2?

A

CD14, CD36 and MbL

33
Q

What proteins promote CpG DNA delivery to endosome-localised TLR9?

A

DNA-binding proteins HMGB1 and RAGE

34
Q

How many lipid chains do you need for most efficient binding of LPS to TLR4?

A

6 lipid chains with 12-14 carbons each

35
Q

What is the process of CD14 and TLR-4 Endocytosis?

A

CD14 mediates TLR4 Endocytosis and interferon expression
CD-14 induced Endocytosis occurs independently of TLR4 signalling

36
Q

What other TLRs can CD14 help?

A

TLR3 - facilitates uptake of poly I:C into TLR3 endosome
TLR7 and 9 - acts as a coreceptor for TLR7 and 9 to promote their signalling

37
Q

What does TLR2 collaborate with?

A

TLR1 and TLR6

38
Q

what does TLR2 with TLR1/6 do?

A

Discriminates between triacyl and diacyl lipopeptides respectively

39
Q

Why is purity of reagents really important?

A

Because there was a study that was activating TLRs and they thought it was serum amyloid A but it was actually the contaminating proteins

40
Q

What receptors recognises flagellin?

41
Q

What are the endosomal TLRs?

A

TLR3, 7, 8 and 9

42
Q

What TLR recognises dsRNA?

43
Q

What innate immune cells is TLR3 not highly expressed in?

A

Neutrophils and plasmacytoid DCs

44
Q

What is TLR-3 deficiency in humans associated with?

A

Herpes simplex virus type 1

45
Q

What is an analogue of dsRNA?

46
Q

How many binding sites do TLRs 7,8,9 have?

A

Two binding sites

47
Q

What does TLR9 bind?

48
Q

What does TLR7 and 8 bind?

49
Q

When is TLR7 dimerisation most efficient?

A

In the presence of ssRNA and free guanosine molecules

50
Q

When is TLR8 dimer formation most efficient?

A

In the presence of ssRNA and free uridines

51
Q

When is TLR9 dimer formation most efficient ?

A

Presence of CpG-containing DNA and free cytosines

52
Q

What happens to TLR3, 7, 8 and 9 when in endosome?

A

They are cleaved within their leucine-rich-repeat containing ectodomains
Both fragments remain associated with one another and are important for inflammatory activity of these receptors

53
Q

Which TLR doesn’t function the same in mice and humans?

A

TLR8 - so it is less well studied than TLR7

54
Q

What is TLR9 highly expressed on?

A

Plasmacytoid dendritic cells

55
Q

What is TIRAP/MAL?

A

A peripheral membrane protein that surveys the inner leaflets of the plasma and endosomal membranes

56
Q

What does TIRAP/MAL signal through?

A

an N-terminal phosphoionsitide binding domain

57
Q

What does TIRAP/MAL contain at its C terminus and what does it do?

A

Contains a TIR domain
Recognises dimerised TIR domains of most TLRs

58
Q

What is the TIR domain essential for in TIRAP/MAL?

A

Signalling by TLRs 2, 4, 7 and 9

59
Q

What is a SMOC?

A

A supramolecular organising centre that is assembled following detection of TIR domain dimerisation

60
Q

What does IRAK stand for?

A

IL-1 receptor associated kinase

61
Q

What does TLR and MyD88 association recruit?

A

IRAK4 that autophosphorylates and phosphorylates IRAK1/2

62
Q

What does the MyD88 complex formation do?

A

Induces association with E3 ubiquitin ligase TNF receptor-associated factor 6 ( TRAF6)

63
Q

What are the 3 pathways triggered through MyD88 mediated signalling?

A
  • NFkappaB activation
  • MAPkinases
  • glycolysis
64
Q

How is nfkappab activated through MyD88 signalling?

A

TRAF6 complexes with TAK1 complex comprising of TAK1. TAK1 then associated with IKK leading to phosphorylation of IKKb, triggering the pathway

65
Q

How are MAP kinases activated with MyD88 signalling?

A

Activation of upstream MAP kinases for Erk1 and 2, p38 and JNK which activate transcription factors AP-1 and CREB

66
Q

How does activation of glycolysis occur from MyD88 signalling?

A

TRAF6 recruits kinase TBK1 that induces glycolysis through phosphorylation of AKT that phosphorylates hexokinase

67
Q

What do all endosomal TLRs need to be transported to the endosome?

A

A chaperone

68
Q

What is the only TLR that will never be affected by MyD88 deficiency?

69
Q

What is gamma interferon only produced by?

A

NK cells and Th1 cells

70
Q

what is type 1 interferon produced by?

A

Every cell

71
Q

What is the only adaptor used by TLR-3?

72
Q

What is TRIF essential for?

A

Induction of genes encoding type I IFNs and IFN-stimulated genes in response to TLR-4

73
Q

What adaptor does TLR4 require?

A

TRAM
Upon detection of dimerised TLR4 in endosome, TRAM interacts with TRIF

74
Q

What does TRIF-dependent signalling in response to TLR4-LPS lead to?

A

Upregulation of cos-stimulatory molecules and MHCII in DCs through production of type I IFNs

75
Q

What is a negative regulator of MyD88?

76
Q

What is a key negative regulator of TLRs?

77
Q

What happens if someone has a defect in MyD88?

A

They are not as sick as expected, are susceptible to a particular group of pathogens

Innate Immunity (7 decks)

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