PRRs

Question 1

How does the immune system determine whether to produce an interferon or inflammatory response to different microbes

Answer 1

type of receptor
localisation of receptor
signalling pathways from receptors

Question 2

how many members are there in the mammalian toll-like receptor family

Answer 2

11-13

10 in humans

Question 3

what type of infection are Toll knockout flies particularly susceptible to

Answer 3

fungal

Question 4

what is the roll of the extracellular leucine rich repeat (LRR) region of TLRs

Answer 4

recognises the ligand

Question 5

to which protein does the LRR region of TLRs share significant homology

Answer 5

IL1 receptor

Question 6

what is the role of the intracellular TIR domain of TLRs

Answer 6

it is a carboxyl region which is responsible for transducing signalling

Question 7

of which type of response are TLRs key inducers

Answer 7

pro-inflammatory

Question 8

which TLRs recognise lipids

Answer 8

TLR1,2,4,6 and 10

Question 9

which TLRs recognise nucleic acid

Answer 9

TLR3,7,8and9

Question 10

which TLRs recognise protein

Answer 10

TLR5

Question 11

to which cells are TLRs mostly localised to

Answer 11

immune cells e.g. Docs and macrophages

Question 12

to where within the cell are TLRs which detect bacterial and fungal components such as proteins and lipids localised and which type of response do they elicit

Answer 12

Plasma membrane,

inflammatory

Question 13

where are TLRs which recognise viral components localised within the cell and what type of response do they elicit

Answer 13

endothelial membrane

interferon response

Question 14

which signalling pathways is the inflammatory response mediated by

Answer 14

NFkB and MAPK

Question 15

what is the role of MyD88 in TLR signalling and describe the signalling pathway it induces

Answer 15

adaptor protein which facilitates the formation of signalling complexes consisting of protein kinases and ubiquitin ligases which modify a number of substrate proteins, culminating in the activation of transcription factors including NFkB. The inhibitory subunit is removed to reveal it’s nuclear localisation signal allowing it to move into the nucleus and bind to promoters to switch on genes involved in inflammation

Question 16

what makes TLR3 different from other TLRs

Answer 16

it is MyD88 independent

Question 17

what does TLR3 detect

Answer 17

dsRNA in endosome (antiviral)

Question 18

which adaptor protein does TLR3 use in place of MyD88

Answer 18

TRIF

Question 19

which pathway does TLR3/TRIF activate

Answer 19

NFkB, in particular switching on interferon regulatory factor 3 which activates IFN

Question 20

describe how TLR4 is able to switch on both an inflammatory and interferon response

Answer 20

when localised to the PM and associated to MyD88 complex it initiates inflammatory response, then it is endocytosed into the cytosol where it activates interferon response

Question 21

what is the basis of next generation vaccines

Answer 21

utilise agonists of toll like receptors

Question 22

to which family of proteins do the Nod1/2 receptors belong to?

Answer 22

nucleotide binding domain LLR family

Question 23

describe the structure of Nod1 and Nod2

Answer 23

they consist of a caspase recruitment domain (CARD), nucleotide binding domain (NBD) and a leucine rich repeat region

Question 24

what response does binding of ligands to Nod1/2 elicit

Answer 24

inflammatory

Question 25

what substrates do Nod1/2 recognise

Answer 25

both recognise breakdown products of peptidoglycal substructures (cell wall). Nod1 sees iE DAP and Nod2 sees myramyl dipeptide (MDP)

Question 26

describe the nod1/2 signalling pathway

Answer 26

1. ligand binding induces dimerisation
2. conformational changes allow card domains to become present
3. recruitment of RIP2 kinase induces ubiquitylation
4. RIP2 recruits TAB_TAK1 complex which phosphorylates IKK and MAP3K complexes
5. this activates MAPK and NFkB pathways

this is a pro inflammatory response

Question 27

which disease is associated with mutations in nod1/2 receptors

Answer 27

chrons

Question 28

what is the consequence of activation of intracellular DNA receptor cGAS

Answer 28

DNA binding activates it to convert ATP and GTP forming a unique version of cGMP which binds STING to activate it. STING is a stimulator of inteferon genes

Question 29

why do intracellular DNA receptors such as cGAS use second messengers?

Answer 29

secondary messengers are able to diffuse through GAP junctions achieving intercellular signalling by activating STING in adjacent cells.
in addition, cGMP can be packaged into new viral particles so upon invasion of new cells uncaring of that particle will immediately alert the cell of invasion before the virus has begun replicating and producing PAMPs