Toll-Like Receptors

Question 1

PAMPs

Answer 1

pathogen-assoc molecular patterns
- common to pathogens but not to mammals
- recognized by receptors of innate immune system
- integral for pathogen survival (structure, function, or replication) so it’s unchanging

Question 2

PAMPs of viruses

Answer 2

glycoproteins = ssRNA, dsRNA, genomic DNA

Question 3

bacteria PAMPs

Answer 3

lipopeptides, lipoteichoic acid, LPS, flagellin, CpG DNA (non-methylated)

Question 4

protozoa PAMPs

Answer 4

GPI anchors, dsRNA, haemozoin

Question 5

the receptors that recognize molecular patterns or motifs on pathogens but not on host

Answer 5

PRR (pattern recognition receptors) such as TLRs (toll-like receptors = surface/endosome)

these cause a signal cellular response, most often inflammation

Question 6

T or F. TLRs are a type of PRR

Answer 6

T

Question 7

where are TLRs found?

Answer 7

in/on dendritic cells or macrophages
- located on cell surface and
- inside cells = endosomes, lysosomes

Question 8

describe the structure of TLRs

Answer 8

exterior = leucine rich repeats = recognize and bind PAMPs

interior = TIR (toll-IL-1 receptor) = activate signalling in cell to generate a response

Question 9

These TLRs are in mice only

Answer 9

11-13

Question 10

these TLRs are in mice and humans

Answer 10

TLR1-10

Question 11

TLR2

Answer 11

LIGAND IS PEPTIDOGLYCAN
in gram pos bacteria, parasites, fungi

Question 12

TLR3

Answer 12

dsRNA in viruses

Question 13

TLR4

Answer 13

LPS in gram neg bacteria

Question 14

TLR5

Answer 14

flagellin in bacteria

Question 15

TLR9

Answer 15

CpG DNA in bacteria/viruses
- unmethylated DNA unique to bacteria/viruses

Question 16

how do TLRs bind?

Answer 16

can be homodimers = TLR4/4, TLR9/9

OR heterodimers = TLR1/TLR2, TLR2/6

Question 17

steps in TLR signalling

Answer 17

LRR recognition of PAMP
dimerization
conformational change in TIR
recruitment of 1-4 adapter molecules
= MyD88, TRIF, TIRAP, and TRAM

Question 18

myeloid differentiation factor 88

Answer 18

• adaptor for IL-1 receptor (pro inflam cytokine)
• MyD88 binds TIR = recruits IL-1 receptor activated kinase (IRAK)
• phosphorylates TNF receptor assoc factor 6 (TRAF6)
• IRAK and TRAF6 dissociate and interact with TAK1
• TAK1 induces NF-kB and AP-1 transcription factors

Question 19

TRIF-dependent signalling

Answer 19

endosomal pathway for TLR3 and TLR4
- TRIF activates TRAF3 and TBK-1-IKKe
- TRAF3 complex phosphorylates IRF7 and IRF3
- IRF7 and IRF3 induce transcription if IFN-a and IFN-B

• appropriate for viruses bc inside cell

Question 20

what does TLR signalling = transcription factors activate the cell to produce?

Answer 20

antimicrobial peptides
cytokines
chemokines
enzymes

these proteins mediate or enhance next step of innate/adaptive immune system

Question 21

cytokine production of MyD88

Answer 21

TNF = vascular permeability, activates macs, induces APRs, fever

IL-1 and IL-6 = induces neutrophil release from BM (immature), enhances lymphocyte activity, vascular permeability, fever, APR, similar to TNF

** ALL PRO-INFLAM **; bacteria

Question 22

TRIF cytokine production

Answer 22

dependent through IRF7 and IRF3

type 1 interferons (INF-a,B)
- inhibit viral replication
- promotes resistance of viral infection to neighbouring cells
- promotes MHC I expression on cells
- activate NK cells

IL-10
- regulate mac and suppress Th1 cells (anti-inflammatory)

Question 23

IL-8

Answer 23

aa chemokine that attracts neuts to site of infection, along with basophils and some lymphocytes

Question 24

defensins

Answer 24

polypeptides with antimicrobial activity = cause permeability to prokaryotic membrane or bind NAs

Question 25

enzymes

Answer 25

nitric oxide synthase (NOS) needed for respiratory burst