Innate Molecules (Innate Sensors, Complement, MHC Molecules, Antigen Processing)

Question 1

Give some basic information about TLRs.

Answer 1

3 domains
- extracellular N-terminal
- middle helix transmembrane
- intracellular C-terminal

homeostasis: exists as monomer or (weak) dimer
activation: homodimers (eg TLR4) or heterodimers (eg TLR1/2)

dimerisation = stability = signalling

leucine rich repeats (LRR): The variability in the number, sequence, and orientation of LRRs among TLRs determines their ligand specificity

TIR domain interacts w signalling molecules

TLRs can be intracellular or extracellular

Question 2

Note some differences between human and mouse TLRs.

Answer 2

TLR10 is human exclusive - recognises triacylated lipopeptides

TLR11, 12, and 13 are mouse exclusive:
- 11 and 12 recognise profilin: found in certain protozoan parasites
- 13 recognises ribosomal RNA

mice express TLR8 but it seems to be non functional

Question 3

Give some more detail about the TIR domains of TLRs?

Answer 3

toll/interleuokin-1 receptor
~ 200 aa

intracellular

these often have weak, transient interactions until TLRs self-associate
- this creates a scaffold that facilitates signal transduction = immune response or cell-death

Question 4

What are the TLR adaptor proteins?

Answer 4

1. MyD88
2. TRIF
3. TIRAP/MAL
4. TRAM
5. TRAF3

TLR signalling largely divided into MyD88-dependent and TRIF-dependent pathways

MyD88: utilised by all TLRs
= activates NK-kB and MAPKs for induction of inflammatory cytokine genes

TRIF is recruited to TLR3 and 4
= promotion of alternative pathway that leads to activation of IRF3, NK-kB, and MAPKs for induction of type I IFK and inflammatory cytokine genes

Question 5

What is the function of NF-kB?

Answer 5

inducible TF

regulates inflammation directly by increasing production inflammatory cytokines, chemokines, and adhesion molecules

also regulates cell proliferation, apoptosis, morphogenesis, and differentiation

Question 6

Give some detail about TLR 1/2 and 2/6.

Answer 6

1/2 detect triacyl lipopeptides
2/6 detects diacyl lipopeptides
= highly expressed cell wall components in gram+ bacteria

can also detect alarmins -> endogenous ligands eg heat shock proteins

signal through MyD88 (TIRAP/Mal facilitates connection to receptor)

downstream signalling triggers SEAP promoter = secretion of alkaline phosphatase (ALP) or induce production of pro-inf cytokines eg TNF a, IL, IFN
– ALP dephosphorylates peptidoglycan, previnting binding to receptors

Question 7

Give some detail about TLR3.

Answer 7

detects viral dsRNA, and polyI:C (dsRNA analogue)

homodimerisation allows for signalling via TRIF/TRAF3 to activate IRF3 (TF) further downstream

strong inducer of type I interferon (IFN)

expression of TLR3 increases with age (may be due to immune response too strong for children to handle?)

Question 8

Give some detail about TLR4.

Answer 8

detects LPS
- uses MD-2, an accessory protein, to assist in detection and dimerisation

extracellular LBP binds LPS monomer -> delivery to soluble or membrane CD14 -> transfer LPS to TLR4/MD-2 complex = homodimerisation -> dimerisation of TIR -> binding of MyD88

this activates TF NF-kB and MAPK -> transcription of pro-inf cytokines

endocytosis of LPS-TLR4/MD-2 complex leads to TRIF/TRAM-dependent pathway -> induction of IRF3 and IFNs

Question 9

Give some detail about TLR5.

Answer 9

detects flagellin

main extracellular receptor interacting w human intestinal microbiota
- expressed in monocytes and immature DCs
- specifically expressed on basal side of intraepithelial cells (IECs)

Question 10

Why is TLR5 specifically expressed on basal side of IECs and what does activation do?

Answer 10

intraepithelial cells

separation from luminal contents, prevents uncontrolled inflammation by symbiotic microbes

activation of TL5 decreases epithelial barrier resistance and reduced expression of tight junction proteins and produce chemokines eg IL-8
–> makes space for, and attracts immunes cells

Question 11

Give some detail about TLR7 and 8?

Answer 11

detect GU-rich short ssRNA in endosomes/lysosomes

• signal through MyD88
• nuclear translocation of AP-1, NF-kB, and IRFs
• phosphorylation of IRFs promote induction of interferon stimulated response element (ISRE), w expression of IFN

== production of pro-inf cytokines

Question 12

Give some detail about TLR9

Answer 12

detects CpG
- unmethylated cytidine-phosphate-guanine
- restricted to bacterial and viral DNA
- mitochondrial DNA following cell stress can activate TLR9

also recognises hemozoin

activated IFN and chemokines
upregulated co-stimulatory molecules on DCs (CD80)

Question 13

What is the cGAS-STING pathway?

Answer 13

cyclic GMP-AMP synthase (cGAS) is a cytosolic receptor that detect cytosolic dsDNA, from bacteria, viruses, or damaged cell

1. detection of dsRNA by cGAS to produce cGAMP from ATP and GTP
2. cGAMP binds to STING dimer present on ER membrane and activates its signalling
3. STING activates the kinase TBK1 to phosphorylate IRF3 which enters nucleus and induces expression of type 1 interferon genes

Question 14

What is AIM2?

Answer 14

AIM2 recognizes dsDNA in the cytoplasm from viral or bacterial infection or mitochondrial DNA released from damaged cells

AIM2 binds to dsDNA via its HIN200 domain
The PYD of AIM2 interacts with the PYD of ASC (adaptor), leading to oligomerization of ASC

ASC recruits and activates pro-caspase-1 by forming a large multiprotein complex.

Active caspase-1 cleaves pro-IL-1β and pro-IL-18 into their mature, secreted forms
Caspase-1 also induces pyroptosis, a form of inflammatory cell death

Question 15

What are NOD-like Receptors (NLRs)?

Answer 15

detect bacterial cell-wall peptidoglycans

NOD proteins reside in cytoplasm in inactive form
binding of bacterial ligands to NOD proteins -> dimerisation (like TLR) induces recruitment of RIP2 -> activates TAK1 > NF-kB activation

have a CARD domain (caspase recruitment)

Question 16

What is the NLRP3 inflammasome?

Answer 16

detect heat shock protein 90 + co-chaperone

pyrin domain instead of a CARD domain

NLRP3 proteins remain as inactive monomers in cytoplasm
– potassium efflux induces dissociation of chaperones that keep NLRP3 in inactive conformation

NLRP3 form oligomers w ASC causing proteolytic cleavage of pro-caspase 1
– recruitment through interaction of ASC CARD and caspase-1 CARD

caspase 1 releases mature inflammatory cytokines such as IL-1 and IL-18 from their proproteins

Question 17

What is the significance of ALUM in the context of the inflammasome?

Answer 17

Alum (aluminium hydroxide) is the most widely used adjuvant used in human vaccines as it is known to activate the NLRP3 inflammasome

Question 18

How does C3b bind to the surface of a pathogen? (alternative pathway)

Answer 18

C3 protein is proteolytically processed to generate a beta chain and an alpha chain held together by disulfide bonds

thioester bond within TED (thioester containing domain) is protected from reacting

cleavage of C3 (by C3 convertase: C3bBb) = C3a + change of conformation of C3b -> allows thioester bond to react w a nucleophilic group on pathogen surface (NH2, OH)

Question 19

How does MBL recognise pathogen carbohydrates? (lectin pathway)

Answer 19

mannose-binding lectin

MBL monomers form trimeric clusters of carbohydrate-recognition domains

complex w serine proteases
- MASP-1, -2, -3

MBL binds w high avidity to mannose and fucose residues

Question 20

How do ficolins recognise pathogen carbohydrates? (lectin pathway)

Answer 20

ficolins have similar structure to MBL (trimeric) but have different carb-binding domain

complex w serine proteases
- MASP-1, -2, -3

ficolins bind oligosaccharides containing acetylated sugars

Question 21

After recognition of carbohydrates, how does the lectin pathway progress?

Answer 21

1. activated MASP-2 associated w MBL or ficolin cleaves C4 -> C4a + C4b
   –> C4b binds microbial surface through binding of its thioester bond to a nucleophilic group
2. C2 is cleaved by MASP-2 to C2a + C2b
   –> C2a complexes w C4b = a C3 convertase
3. C4bC2a cleaves C3 -> C3a and C3b
   –> C3b binds microbial surface or C3 convertase
   –> one molecule of C4bC2a can cleave up to 1000 molecules of C3

Question 22

What is C1 composed of? (classical pathway)

Answer 22

C1q: recognition of antigen bound antibodies

C1r and C1s: cleave C4 and C2

C1q:Cr1_2:C1s_2

Question 23

How is C1 activated? (classical pathway)

Answer 23

• multiple Ig (typically IgG1 and IgM) are needed for C1 activation, these bind to C1q
• movement of Fc domain opens up C1q-binding sites
• the number, and position, of Ig will determine the opening, thus, the strength of the pathway
• gC1q will rotate inward (heads), leading to opening of the CLR (stalk)
• C1rC1s will pass from inactive 8 form to active S-shaped conformation

Question 24

After activation of C1, how does the classical pathway progress?

Answer 24

autocatalytic activation of C1r and C1s in turn cleaves C4 and C2 into larger (C4b, C2a) and smaller (C4a, C2b) fragments
–> C4bC2a = a C3 convertase

C4bC2a cleaves C3 -> C3a and C3b
–> C3b binds microbial surface or C3 convertase

Question 25

What is tick over in the alternative pathway?

Answer 25

how the alternative pathway begins

spontaneous hydrolysis of the thioester bond in TED due to instability in plasma (aqueous)
–> resulting C3(H2O, like C3b) binds factor B

factor D cleaves factor B into Ba + Bb <- still bound to C3(H2O)

C3(H2O)Bb complex = a C3 convertase

this cleaves C3 into C3a and C3b -> C3b rapidly inactivated unless it binds cell surface
–> factor B binds noncovalently to C3b on a cell surface and is cleaved to Bb by factor D

Question 26

What is properdin? (alternative pathway)

Answer 26

glycoprotein found in plasma that is mainly produced by leukocytes and can positively regulate AP activity by stabilising C3bBb convertase
eg activated neutrophils at site of inflammation

C5a generation induces increased properdin secretion ie positive feedback loop

Question 27

How does bacterial PGN enter the cell to activate NOD1 and NOD2 receptors?

Answer 27

1. some bacteria can deliver PGN into the host cell cytoplasm through its secretion system
2. uptake of outer membrane vesicles (OMVs) released by Gram-negative bacteria facilitates internalization of PGN
3. extracellular PGN fragments can enter the host cell through endocytosis and transported to the cytosol through lysosomal membrane transporters

Question 28

What is iC3b?

Answer 28

inactivated C3b

produced when C3 is cleaved by complement factor I

cannot form convertases, but can still act as an opsonin and anaphylatoxin

stimulates phagocytosis via macrophages and DCs through binding to CR3 or CR4

stimulates phagocytosis of circulating pathogens via tissue resident macrophages through binding to CRIg

Question 29

How do C3a and C5a increase vascular permeability?

Answer 29

activate mast cells which release TNFa

C5a more active than C3a

Question 30

How can C5a enhance the phagocytosis of pathogens?

Answer 30

When only C3b coated on bacterium binds to CR1, bacteria are not phagocytosed

C5a can activate macrophages to phagocytose by binding to C5aR1

Question 31

How is C5 convertase formed in the classical and lectin pathways?

Answer 31

some of the C3b fragments generated by C4bC2a C3 convertase bind to it, forming C4bC2aC3b = C5 convertase

Question 32

How is C5 convertase formed in the alternative pathway?

Answer 32

some of the C3b fragments generated by C3bBb C3 convertase bind to it, forming C3bBbC3b = C5 convertase

Question 33

How is the membrane attack complex formed (MAC)?

Answer 33

formed during the terminal pathway of complement activation

1. C5b, generated by C5 convertase, binds C6 and C7
2. C5b67 complexes bind to pathogen membrane via C7
3. C8 binds to complex and inserts into cell membrane
4. C9 molecules bind to the complex and polymerise
5. Up to 16 C9 molecules bind to form a pore in the membrane

Question 34

How is the complement system regulated?

Answer 34

• C1 inhibitor (C1INH) dissociates C1r and C1s from the active C1 complex
• DAF, C4BP, and CR1, can displace C2a from C4bC2a complex
  – then C4b bound to any of these is cleaved by a soluble protease I to inactive forms, C4d and C4c
• CD59 prevents final assembly of MAC on host cells at the C8 to C9 stage

Question 35

What is MHC?

Answer 35

major histocompatibility complex

discovered in mice (H-2), then 20 years later in humans (HLA) as genetic locus responsible for rapid graft rejection

large genomic regions that determine “transplantation antigens”

thousands of alleles that are matched by tissue typing to avoid rejection

MHC molecules detect infections inside cells, cancers, and extracellular pathogens

high polymorphisms mostly driven through a molecular arms race w pathogens

Question 36

What are classical MHC molecules?

Answer 36

• highly polymorphic
• present peptides to T cells
• have wide tissue distribution:
  – class I expressed in all nucleated cells
  – class II expressed on professional and facultative APCs
• are conserved among all jawed vertebrates

Question 37

What are non-classical MHC molecules?

Answer 37

• differ in one or more of attributes of classical MHC molecules
• are derived from classical molecules at different times in evolutionary history

Question 38

What is cross presentation, and in which cell does it occur?

Answer 38

exogenous antigens are processed and presented on MHC class I molecules

enables activation of CD8+ T cells where antigen source did not directly infect the presenting cell

cDC1 is cell that can most efficiently perform cross presentation
– cDC2 also can but to a much less degree

Question 39

What is the structure of peptide binding regions of MHC class I?

Answer 39

peptides bound to class I molecules are 8-10 aa long
– longer peptides tied down at the ends and bulge in the middle

peptides have a few anchor residues which bind into deeper pockets which stabilise peptide binding
– because fewer variety of intracellular antigens
– peptides generated from proteosome

P2 binds pocket B - commonly a leucine
P9 binds pocket F - hydrophobic residue eg proline, leucine

Question 40

What is the structure of peptide binding regions of MHC class II?

Answer 40

peptides lie flat and hang out the ends, w multiple anchor residues bound to more pockets
- focussed on a particular epitope on peptide it recognises, the rest doesn’t matter and hangs out the ends
- peptides generated from endocytic vesicles

pockets P1, P3, P6, and P9 are important for binding anchor residues

Question 41

Give examples of non-classical class I-like molecules?

Answer 41

HFE
– sequesters iron from pathogens
– non-polymorphic, widely expressed
– in MHC or extended MHC

EPCR
– protein C receptor in clotting
– not polymorphic, on endothelial cells
– used by some malaria strains to bind to blood vessels
– genes outside of MHC

MR1
– present bacterial metabolites
– monomorphic, widely expressed
– genes outside of MHC

Question 42

What are the classical class I molecules?

Answer 42

HLA-A, -B, -C
– present peptide to T cells
– NK ligand
– highly polymorphic, widely expressed

Question 43

What are the non-classical class II-like molecules?

Answer 43

DM
– chaperone, peptide editor
– non-polymorphic
– expressed in APCs

DO
– binds to and inhibits DM
– non-polymorphic
– expressed in some APCs (B cells)

DQ2
– no known function
– monomorphic
– expressed in DCs in skin (Langerhans cells)

Question 44

What is the structure of the MHC gene regions?

Answer 44

MHC organisation is similar among placental animals
– class I regions v different
– class II regions v similar
– class III are similar as they are not responsible for immune function

in humans there are also extended class I and II regions

class I and II genes separated by class III, thought to be evolutionary mistake

many more non-classical class I molecules in mice than humans

Question 45

What is the function of ubiquitin?

Answer 45

ubiquitin ligase creates chains of ubiquitin on target protein which result in different outcomes
– degradation
– signal transduction
– cell death protection
– DNA repair

different types of ubiqutination
– different bond types (phosphorylation, acetylation)
– branched
– homotypic, heterotypic

Question 46

What is the constitutive proteasome?

Answer 46

found in most cells

AAA ATPases act as chaperones and unfold substrates

• four stacks of rings, each composed of 7 related proteins
• two identical rings of a subunits form gates
• two identical rings of b subunits include 3 threonine proteases

Question 47

What is the immunoproteasome?

Answer 47

present in mTECs, DCs, T cells

IFNy upregulates class I and II presentation

for class I:
- upregulation of class I a chains, B2-microglobulin, TAP1, TAP2
- better C-termini peptides for class I molecules

Question 48

What is the thymoproteasome?

Answer 48

present in cTECs, important for positive selection of T cells
– have beta5t subunit
– produces self peptides from digested self proteins

Question 49

What is the role of cytosolic proteases after peptides have undergone proteasome degradation?

Answer 49

trims peptides to optimal length for optimal antigen presentation, N terminal or C terminal extensions

eg tripeptidyl peptidase II (TPPII)

Question 50

What is the structure of TAP?

Answer 50

ATP-binding cassette (ABC) transporter

TAP1 and 2 (heterodimer) each composed of a:
– tapasin-binding domain
– transmembrane peptide-binding domain
– nucleotide-binding domain (NDB)

each ATP binding site is split between the NDBs of TAP 1 and 2
the two NDBs must come together to hydrolyse one ATP

Question 51

What is the function of TAP?

Answer 51

important for class I presentation, transports peptides from cytosol into ER where they can be loaded onto MHC class I molecules

the C-terminal specificity of the TAP corresponds w the specificity of the class I molecule at pocket F
– the immunoproteasome produces peptides that fit the specificity of the class I molecule at pocket F

so TAP can only transport peptides produced by the immunoproteasome

Question 52

What are the steps of the antigen presentation pathway for class I molecules (steps 1-5)?

Answer 52

1. translation of class I heavy chain into ER lumen through the Sec61 translocon complex, w co-translational N-linked glycosylation (one particular very important for quality control (QC))
2. heavy chain binds to calnexin, a chaperone which prevents premature aggregation or misfolding, w glucosidases trimming N-linked glycan
3. this trimming allows proper folding of heavy chain which loses calnexin and binds B2-microglobulin in the ER
   – without this, the heavy chain is not stable and cannot present antigen
4. immature class I molecule (without peptide) associates with the peptide loading complex (PLC) on the ER lumen, includes:
5. Meanwhile, TAP has pumped peptides into ER lumen

Question 53

What are the steps of the antigen presentation pathway for class I molecules (steps 6-9)?

Answer 53

6. ERAPs have trimmed the N-termini of peptides
7. in the PLC, tapasin stabilises class I molecules without peptide and allows cycles in which peptides bind and fall off
   – tapasin holds MHC molecule in a peptide-receptive conformation
   – peptides w weak affinity bind and fall off
8. class I molecules bound to peptide w appropriate affinity are released from PLC
9. released class I molecules are subject to another round of quality control by the UGT1-TAPBPR system, and sent either back to the PLC or to the GA and then to the cell surface

Question 54

What is the function of ERAPs?

Answer 54

endoplasmic reticulum aminopeptidases

trims peptides bound to class I molecules to optimal length for optimal antigen presentation, specifically N-terminal extensions

eg ERAP 2, trims longer peptides before ERAP 1 refines them to optimal final length

Question 55

What is the function of the UGT1-TAPBPR quality control system?

Answer 55

the class I molecule is released from the PLC through removal of the last glucose from the N-linked glycan, now it undergoes a second round of quality control

the lectin UGT1 binds the N-linked glycan and recruits tapasin via TAPBPR
– if the peptide falls of while tapasin is bound, then N-linked glycan is re-glucosylated and the class I molecule binds back to PLC

rinse and repeat until a peptide with high enough affinity is bound

Question 56

What is the PLC

Answer 56

peptide loading complex

– Tapasin: chaperone that connects MHC class I molecule to TAP
covalently binds to ERp57

– Calreticulin: chaperone that stabilizes immature MHC class I molecule during peptide loading

– ERp57: thiol oxidoreductase that assists in folding and prevents improper disulfide bond formation in the heavy chain

– TAP1/TAP2: TAP transporter complex pumps peptides from the cytosol into the ER lumen, where they can bind to MHC class I molecules

Question 57

Describe different methods used by viruses to evade the MHC class I antigen presentation pathway.

Answer 57

– HCMV US2 and US11 dislocate the MHC class I heavy chain into the cytosol where it is degraded by the proteasome

–HHV7 U21 diverts MHC class I molecules to the lysosome

– HIV Nef down-regulates MHC class I molecules from the PM, sequestering them in the trans-golgi network (TGN) through blockage of transport

Question 58

What are the first steps for canonical antigen presentation on MHC class II molecules?

Answer 58

1. class II a and b chains co-translationally glycosylated as they enter the lumen of the ER and then associate w invariant chain (Ii) trimer -> protects from peptide-binding in ER

2a. Ii-MHC class II delivered to PM and endocytosed in a clathrin coated vesicle which is targetted to an early endosome

2b. exogenous antigen binds receptor and is endocytosed in a clathrin coated vesicle where it targetted to an early endosome

3. early endosome fuses to the MIIC which contains DM molecules
4. proteases eg cathepsins digest Ii molecule to leave class II invariant peptide (CLIP) in the binding groove of class II molecules, and proteases digest antigen

Question 59

What is the function of the ATP-dependent H+ ion transportation in the context of MHC class II presentation?

Answer 59

present in early endosomes, which makes the endosome more acidic as it matures
– deeper into the cytoplasm, the more acidic the endosome

this allows cathepsins to carry out their enzymatic activity

also promotes the exchange of CLIP for antigenic peptides w help from DM

Question 60

Why is CLIP called a “universal binding peptide”?

Answer 60

CLIP binds to the MHC class II groove in a non-specific manner, fitting into a wide range of MHC class II alleles

uses methionines as anchor residues, not high affinity binding so can be exchanged

Question 61

How is antigen uptake and subsequent degradation performed in different cell types?

Answer 61

phagocytosis (macrophages)

macropinocytosis (DCs): Non-specific uptake of extracellular fluid containing soluble antigens

B cells (also DCs and macrophages) endocytosis

degradation by a variety of proteases, glycosidases etc that depend on cell type and organelle

digestion can destroy epitope, so v high in macrophages but lower in DCs and B cells

IFNy inducible lysosomal thiol reductase (GILT) reduces disulphide bonds to allow protein to be unfolded

Question 62

What are the 5 steps of peptide loading in the MIIC?

Answer 62

Step 1: CLIP is bound in DR groove and P1 pocket, which prevents premature antigen binding

Step 2: DM (chaperone) interacts with DR -> triggers a conformational change
– during this transition, the N terminus of CLIP detaches from the groove, and DR rotates away from the P1 pocket, allowing it to become available for interactions with DM

Step 3: DM stabilizes empty DR, and DR protects the hydrophobic P1 pocket.

Step 4: Rapid binding of peptides to partially accessible groove; peptides that do not successfully compete with DR residues for P2 site and P1 pocket are not stably bound.

Step 5: Binding of the peptide N terminus reverses conformational changes and results in DM dissociation.

Question 63

What is DO?

Answer 63

expressed in B cells, medullary thymic epithelial cells (mTECs), and certain DC subsets

bind strongly to DM as a competitive inhibitor of classical class II binding

Its exact function seems to still be a topic of ongoing research but one hypothesis says DO might have a role in negative selection in the thymus due to is selective expression pattern

Question 64

How do bacteria evade the MHC class II antigen presentation pathway?

Answer 64

– M. tuberculosis secretes SapM (secretory acid phosphatase M) that can hydrolyze phosphoinositides, disrupting vesicle acidification and preventing effective peptide loading

– Helicobacter pylori: VacA has been found to interfere with proteolytic processing by B-cells and to specifically inhibit the antigen presentation by newly synthesized MHC class II

– S. typhimurium inhibits surface expression of class II molecules through ubiquitination, performed by T3SS effector proteins

Question 65

What is the pathway for cytoplasmic cross presentation for class I molecules?

Answer 65

occurs in cDC1

the phagosome is created from the ER, so it contains many ER proteins, such as the sec61 complex, part of ER-associated protein degradation (ERAD)
– this complex is involved in translocation, movement of peptides out of ER and into cytosol which are targeted for degradation

– in this case, antigens translocated out of phagosome and into cytosol. this targets antigen to the immunoproteasome where the antigens will proceed through the MHC class I presentation pathway

Question 66

What are CLRs?

Answer 66

C-type lectin receptors, PRRs that recognise different carbohydrates on bacteria, viruses, and fungi in a calcium-dependent manner eg
– Dectin-1: β-glucans (fungal cell walls)
– DC-SIGN: Mannose and fucose on pathogens (e.g., HIV, M. tuberculosis)

Question 67

What are RLRs?

Answer 67

Rig-I-like Receptors which detect cytoplasmic viral ssRNA containg terminal 5’ triphopsphate

work w MDA5
– both have caspase activation and recruitment domains (CARDs) in tandem orientation

signal via MAVS (mitochondrial antiviral signalling proteins) on mitochondrial membrane

activation through IRF3/IRF7/NfkB

Question 68

What is the function of type I interferons?

Answer 68

e.g., IFN-α and IFN-β

Induce expression of interferon-stimulated genes (ISGs) that inhibit viral replication and spread
Promoting RNA degradation and inhibiting protein synthesis in infected cells.

Enhance NK cells and CTLs to eliminate infected cells

Increase antigen presentation by upregulating MHC class I molecules on cells, improving recognition by CD8+ T cells

Question 69

Potassium efflux causes dissociation of chaperones from NLRP3 proteins allowing formation of the NLRP3 inflammasome. What causes the potassium efflux?

Answer 69

high extracellular Ca2+ activates NLRP3 acting as particulate matter, i.e. triggering K+ efflux

introducing phagocytosis inhibitors strongly impairs both the efflux of K+ and NLRP3-dependent IL-1β secretion triggered by particulate matter