Toll-like receptors

Question 1

What are toll like receptors?

Answer 1

• a class of proteins that play a key role in the innate immune system
• come from our germline
• single, membrane-spanning, non-catalytic receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes
• Once these microbes have breached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses

Question 2

Does TLR signaling turn on inflammation?

Answer 2

yes

Question 3

How do innate cells respond to an infection?

Answer 3

• phagocytosis
• antimicrobials
• cytokines and chemokines
• antigen presentation

Question 4

What are pathogen associated molecular patterns (PAMPs)?

Answer 4

• components of the microbe

- recognized by PRRs

Question 5

What are pattern recognition receptors (PRRs)?

Answer 5

• recognize microbial PAMPs
• include TLRs
• distinguish self from non-self
• can be secreted, on cell surface or intracellular

Question 6

What are the functions of PRRs?

Answer 6

• activation of pro-inflamatory signaling
• opsonization
• coagulation
• apoptosis
• complement activation
• phagocytosis

Question 7

What do toll like receptors recognize?

Answer 7

multiple structurally unrelated PAMPs

Question 8

What is the TLR domain structure?

Answer 8

Extracellular - leucine-rich repeats (LRR)

Intracellular - Toll/interleukin-1 receptor domain

Question 9

What TLR recognizes triacyl lipopeptide and what adapters are activated?

Answer 9

• TLR1 and TLR2

- TIRAP and MyD88 -> inflammatory cytokines

Question 10

What TLR recognizes diacyl lipopeptide and what adapters are activated?

Answer 10

• TLR2 and TLR6

- TIRAP and MyD88 -> inflammatory cytokines

Question 11

What TLR recognizes dsRNA and what adapters are activated?

Answer 11

• TLR3

- Trif -> inflammatory cytokines and Type I IFN

Question 12

What TLR recognizes LPS and what adapters are activated?

Answer 12

• TLR4
• TRAM and Trif -> inflammatory cytokines and Type I IFN
• TIRAP and MyD88 -> inflammatory cytokines

Question 13

What TLR recognizes ssRNA and what adapters are activated?

Answer 13

• TLR7 and TLR8

- MyD88 -> inflammatory cytokines and Type I IFN

Question 14

What TLR recognizes Flagellin and what adapters are activated?

Answer 14

• TLR5

- MyD88 -> inflammatory cytokines

Question 15

What is the bacterial component on gram-negative bacteria that stimulates innate immunity?

Answer 15

lipopolysaccharide (LPS)

Question 16

What is the bacterial component on gram-positive bacteria that stimulates innate immunity?

Answer 16

• lipoteichoic acid

- peptidoglycan

Question 17

What are innate genes induced by TLR signaling?

Answer 17

• inflammatory cytokines
• chemokines
• antimicrobials

Question 18

What are adaptive genes induced by TLR signaling?

Answer 18

• MHC

- co-stimulatory molecules

Question 19

What happens when a TLR binds to a ligand?

Answer 19

• dimerization of extracellular LRR domains

- signaling by intracellular TIR domains

Question 20

Where are TLRs that recognize bacteria or fungi?

Answer 20

cell surface

Question 21

Where are TLRs that recognize DNA or RNA?

Answer 21

endosome

Question 22

Which TLR moves from the surface to the endosome?

Answer 22

TLR4

Question 23

Why are TLR3, 7, 8, 9 in the endosome?

Answer 23

intracellular localization facilitates recognizing viral DNA and ssRNA and prevents recognition of self - prevents autoimmune disease

Question 24

What makes sure TLRs are delivered to the right place?

Answer 24

Unc93b1

Question 25

Can mutations in genes that regulate TLR3 transport/localization affect human disease as well as mutations in TLR3?

Answer 25

yes, mutations in Unc93b cause the same disease as mutations in TLR3

Question 26

What transcription factors do TLR signaling activates?

Answer 26

- NFκB - AP-1 - IRF

Question 27

What are the two adaptor proteins of TLR signaling?

Answer 27

- Trif - MyD88 - build up signaling pathways

Question 28

What are the two TLR4 signaling pathways?

Answer 28

cell surface - Myd88 dependent | endosome - TRIF dependent -> delayed

Question 29

Describe the TLR4 signaling Myd88-dependent pathway.

Answer 29

- LPS stimulates TLR4-MD2 dimerization - recruits Myd88 - Myd88 recruits kinases (IRAK-4, IRAK-1, IRAK-2) - ligase Taf6 recruited -> activates MAPKKK TAK1 - TAK1 activates IKK complex, which phosphorylates IκB - IκB is ubiquinated and degraded -> releases NFκB - NFκB translocates into the nucleus

Question 30

What are negative regulators for TLR4?

Answer 30

Many places where they can turn the pathway off

Question 31

What happens when IRAK-4 is mutated?

Answer 31

- recurrent bacterial infections (because TLR4 pathway) | - no further infections after 8 yrs

Question 32

What are three TLR pathways that can be used as targets for treatment?

Answer 32

Agonists - enhancing immunity to infectious disease - enhancing vaccine efficacy Antagonists - treating inflammatory diseases