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Immunology > Lec 6: Cellular Innate Responses > Flashcards

Lec 6: Cellular Innate Responses Flashcards

1
Q

Is Innate immunity specific?

A

No! it in the host cells first active defense against infection

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2
Q

What PRRs are the innate immune system mediated by

A 
TLRs
RLRs
NLRs
CLRs
ORphan receptors
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3
Q

What transcription factors are activated by the innate immune response

A

IRFs and NFkB

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4
Q

Intrinsic immunity

A

constitutively passive activity, but expression enhanced by innate immune signaling

Produce proteins that negate pathogens and pathogen assembly

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5
Q

Viral restriciton factors produced by the intrinsic immune response

A

Tetherin
APOBEC
TRIM5alpha
many more

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6
Q

PAMPS (examples)

A 
bacterial or viral proteins
bacterial or viral DNA
viral RNA
foreign glycans
toxins
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7
Q

DAMPS (examples)

A

damaged cells

host proteins, and heat shock protiens
host RNA and DNA in the wrong compartment

Purine metabolites (ATP, uric acid) in the extracellular space

hyaluronan fragments

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8
Q

How can PAMPS and DAMPS be hidden

A

PAMPS hidden by glycosylated viruses

DAMPS hidden by apoptotic bodies

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9
Q

TLR signalling

A

cell surface or endosomal location

ligand binding and activation causes TLR homo or hertero dimer formation

ultimately IFN, ISGs and pro-inflammatory genes are induced

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10
Q

PRR recycling

A

initiation of signalling cascades when endocytosed

put back onto cell surface or endosome

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11
Q

What TLR ADAPTOR do bacterial and viral DNA bind to, where is the TLR located

A

MyD88 adaptor protein in the endosome

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12
Q

TLR ligands

A

bind exogenous PAMPS and endogenous DAMPS

key contribution to the pathogenesis of chronic inflammatory disorders

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13
Q

RLR signaling

Location, adaptor protein, oligerimization and what genes are induced

A

cytoplasmic location

Ligand binding and activation induces RLR interaction with adaptor (MAVS/IPS) on mitochondria surface

Signalling requires formation of RLR oligomers

Ultimately IFN, ISGs and pro-inflammatory genes are induced

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14
Q

RLR recognition

A

host RNA has very specific strucutre
=no RNA-DNA duplexes
=multi-structure motifs
=capping ?

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15
Q

RLR recognition

A

host RNA has very specific strucutre
=no RNA-DNA duplexes
=multi-structure motifs
=capping ?

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16
Q

What do RLR receptors recognize

A

helicases so they can unwind DNA/RNA

Helicase and CTD domain bind RNA
5’ PPP RNA
duplex RNA structures such as loops and hairpins

CARD domains
mediate interaction with adaptor protein = MAVS

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17
Q

Host cell vs Viral capping

A

host cell capped with a polyA on 3’ end

single 5’ phosphate capped with capping proeins

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18
Q

RLR ligands

A

unusula RNA structure or modificaiton

discriminate between virla and endogenous RNA based on secondary structure and modificaitons

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19
Q

why do RLRs not bind host mRNA

A

?

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20
Q

Requirements of a vaccine

A

and antigen and an adjevent to activate the immune system

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21
Q

NOD1 and NOD2 sense what

A

bacterial peptidoglycan and adjuvants

NLR receptor

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22
Q

NLRC4 and NAIP5 sense what

A

bacterial flagellin

NLR receptor

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23
Q

NLRP3 senses what

A

vaccine adjuvant = Al(OH)3

NLR receptor

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24
Q

how do NLRs work in synergy with TLRs

A

signal 1 - causes expression of pro-inflammatory gens

25
Q

NLR signaling and inflammasomes,

Priming and activation

A

Priming:
NOD1 and NOD2 activate proinflammatory gene transcription (signal 1)

Activaiton:
NLRP3 (or other) inflammasomes activate caspase 1 which cleaves the pro-form of cytokines IL-1beta and IL-18 into their active forms

26
Q

NLR ligands

A

Large PRR family with 22 members in humans, even more in mice

cytoplasmic sensors or adaptor proteins

27
Q

DNA sensors

A

dont fit neatly into one group

sensors DAI, cGAS and AIM2 detect cytoplasmic DNA

PAMP or DAMP derived activators

28
Q

DAI and cGAS activate

A

IRFs and NFkB signalling (similar to TLR or RIG)

29
Q

AIM2 activates

A

adaptor protein ASC and drives inflammasome activation

similar to NLR

30
Q

CLR singnalling

A

receptors bind carbohydrates

31
Q

IL-10

A

immunosupressive

32
Q

How does the innate immune system react to PRR activaiton

NFkB

A

transcription factor for IFN-responsive genes and pro-inflammatory genes

33
Q

How does the innate immune system react to PRR activaiton

IRFs

A

interferon response factors

transcription factor for IFN-responsive gens

34
Q

How does the innate immune system react to PRR activaiton

IFNs

A

interferons (IFNa/IFNb/IFNg)

anti-viral cytokines that elicit the activation of hundreds of downstream genes for cellular protection against pathogens

35
Q

How does the innate immune system react to PRR activaiton

pro-inflammatory cytokines

A

promotes an inflammatory response

36
Q

How does the innate immune system react to PRR activaiton

ISGs

A

hundreds of host genes for cellular protection against pathogens

includes restriction factors

37
Q

Can you describe first and second wavve interferon signalling

A

?

38
Q

Interferon

A

cytokines that initiate antiviral and anti-tumor responses

39
Q

how do inferferons interfere with viral replicaiton in host cells

A

activate immune cells, up-regulate antigen presentation, initaiate cellular antiviral pathways

promote symptoms such as fever and aching muscles during infection

40
Q

Type 1 IFNs

A

innate:
All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α/β receptor (IFNAR) that consists of IFNAR1 and IFNAR2 chainstype I interferons are produced when the body recognizes a virus that has invaded it. They are produced by fibroblasts and monocytes. However, the production of type I IFN-α is inhibited by another cytokine known as Interleukin-10. Once released, type I interferons bind to specific receptors on target cells, which leads to expression of proteins that will prevent the virus from producing and replicating its RNA and DNA

IFNb = first wave

IFNa = second wave

41
Q

Type 2 IFNs

A

IFN lambda

This is also known as immune interferon and is activated by Interleukin-12. Type II interferons are also released by cytotoxic T cells and type-1 T helper cells. However, they block the proliferation of type-2 T helper cells. The previous results in an inhibition of Th2 immune response and a further induction of Th1 immune response.

macrophages and adaptive T cell response

42
Q

Type 3 IFNs

A

innate:

Signal through a receptor complex consisting of IL10R2 (also called CRF2-4) and IFNLR1 (also called CRF2-12). Although discovered more recently than type I and type II IFNs, recent information demonstrates the importance of Type III IFNs in some types of virus or fungal infections

IFNg = first wave

IL-28 = second wave

43
Q

Can you name an ISG and its function?

A

?

44
Q

ISGs

A

genes that are stimulated by transcription factors associated with interferon signaling, such as IRFs and NFkB

45
Q

First wave IFN signalliing is mediated by

A

PRRs and secretion of cytokines

46
Q

First wave IFN initiates what

A

anti-viral response within an infected cell

inside and infected cell
produces IFNs and ISGs

47
Q

Second wave IFN

A

is a postive amplification loop

propagates anti-viral responses throughout the cells of an infected tissue

Autocrine or paracrine effects
produces more IFNs and ISGs

48
Q

How much IFN is enough

A

Too much, or not shut off =
Death and or tissue damage

Too little =
pathogen not killed and chronic inflammation

49
Q

Restriction Factors

A

proteins and enzymes that limit the replication of pathogens in host cells

limits pathogen replication

are expressed at basal levels and can be induced by IFN signalling cascades -> PRR signaling boosts them

Part of a host cell’s intrinsic anti-pathogen immunity measures

50
Q

Trex

A

example of a restriction factor

degrades cytoplasmic DNA

Humans that have a mutant version of Trex1 mount chronic anti-viral responses, due to presence of ERV DNA

= endogenous retrovirues

51
Q

Can you name some vrial restriction factors and their functions?

A

? see her review article

52
Q

Innate immune system evasion stratagies

A

degradation of key proteins (viruses can minimize the effectiveness of restriction factors)
sequestration of key proteins
interrupting protein-protein interactions
modulating post-translational modificaitons

53
Q

Tetherin and HIV

A

teherin is a viral restriction factors that binds to retroviral virions

blocks vrius release from the cell surface

activates an innate immune response

counteracted by HIV

54
Q

HIV protease is a potent inhibitor of innate immune responses

A

is an apartic protease

Introduction of HIV-protease inhibitors has cause a marked decline in HIV-linked OI’s

HIV-protease also has a direct effect on the RIG-I signalling pathway, (sends it to the lysosome for degrredation)= why redundancy is important!

55
Q

What set of TF drive Type 1 interferon signaling

A

done by JAK-STAT pathway

STAT is a TF

maybe it is stat5?

56
Q

Compare and contrast the pathways of:
TLRs
RLRs
NRLs

A

?

57
Q

Explain how innate immune signalling cascades can work together to boost the innate immune response, give and exammple

A

(TLR and NRL singlling to drive phase 1)

put more doe

58
Q

What mechanisms can pathogens use to evade cellular innate immune responses, give an example

A

?

59
Q

What are the three key steps for driving the innate immune response?

A

?

Immunology (23 decks)

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