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Infection and immunity > 25. Viral Evasion of the Innate Immune Response > Flashcards

25. Viral Evasion of the Innate Immune Response Flashcards

1
Q

what is the innate immune response?

A

the first line of defence against infection

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2
Q

what can the innate immune response cause?

A

most of the disease symptoms

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3
Q

what encodes innate defence cells?

A

germ-line cells that arose early in multicellular evolution

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4
Q

how does innate immunity distinguish self from non-self (viruses)?

A

biochemical characterises:
- unusual polymers on viral particles
- distinctive cell surface components
- presence of dsRNA

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5
Q

what accompanies the innate immune response?

A

the inflammatory response by the production of pro-inflammatory cytokines

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6
Q

what causes inflammation?

A

Unnatural cell damage like necrosis

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7
Q

what are the innate interferons?

A

Type 1
type 3

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8
Q

what are type 1 interferons?

A

cytokines that target and are produced by all nucleated cells, particularly produced by dendritic cells

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9
Q

what are type 3 interferons?

A

very similar to type 1 interferons but more restricted to epithelial cells

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10
Q

what are the 2 type 1 interferons?

A

IFNa and IFNb

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11
Q

how many types of interferon b are there?

A

1

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12
Q

how many types of interferon a are there?

A

around 13

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13
Q

why will different people have slightly different interferon responses?

A

small genetic variation in the interferon genes that can effect the response making some people more susceptible to disease

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14
Q

what are the 3 steps of the interferon system?

A
  1. Sensing
  2. Signalling
  3. Antiviral state
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15
Q

what receptors are involved in sensing?

A

PRR especially TLR and RIG I
intracellular receptors have a larger role in viral infections

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16
Q

what is the result of sensing?

A

the transcription and translation of the type 1 interferon genes that are then secreted

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17
Q

what does signalling result in?

A

induction of interferon stimulate genes and the creation of an antiviral state
over 300 genes

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18
Q

what is the race to nearby cells between?

A

the interferons and viral particles

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19
Q

what creates the interferon antiviral state?

A

expression of interferon stimulated genes that make gene products the prevent things like viral replication or assembly

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20
Q

what is important in sensing although it is not fully understood?

A

recognition of viral components by TLR
recognition of intracellular viral RNA/dsRNA by RIG-I like receptors
recognition of intracellular viral DNA by cGAS/STING

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21
Q

what TLRs are specific for viral detection?

A

TLR3
TLR8
TLR9
sometimes TLR4

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22
Q

what signalling pathway does TLRs activate?

A

NF-kB pathway to activate NF-kB transcription factor to enter the nucleus and stimulate cytokine production

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23
Q

what are IRF3 and IRF7?

A

transcription factors that activate type 1 interferon response

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24
Q

what activates IRF3 and IRF7?

A

TLR signalling

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25
Q

what does TLR3 recognise?

A

dsRNA

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26
Q

what does TLR7/8 recognise?

A

viral ssRNA

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27
Q

what does TLR9 recognise?

A

Hypomethylated CpG DNA

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28
Q

where is TLR3 expressed?

A

Macrophages
dendritic cells
B cells
intestinal epithelium

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29
Q

where is TLR4 expressed?

A

Macrophages
dendritic cells
Mast cells
intestinal epithelium

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30
Q

what does TLR4 recognise?

A

specific viral proteins

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31
Q

where is TLR7 expressed?

A

macrophages
B cells
plasmacytoid dendritic cells

32
Q

where is TLR8 expressed?

A

macrophage
neutrophils

33
Q

where is TLR9 expressed?

A

macrophage
plasmacytoid dendritic cells
B cells
NK cells
microglial cells

34
Q

how can a virus trigger TLR3 in the endosome?

A
  1. premature disassembly exposing the genome
  2. vesicles containing viral components fusing with the endosome
  3. uptake of the viral genome from the environments
35
Q

what is the signalling cascade for TLR3 and TLR4 sensing?

A
  1. TLR detects viral components
  2. IkB kinase degrades IkB which then dissociates from NF-kB to activate it
  3. NF-kB can travel to the nucleus
  4. IRF3 is phosphorylated and also enters the nucleus
  5. some other cell specific responses like AP1 also enter the nucleus
  6. All the transcription factors trigger the production of cytokines including interferons
36
Q

what type of cytokines do NF-kB and AP1 trigger production of?

A

general pro inflammatory cytokines

37
Q

what type of cytokines do NF-kB, IRF3 and AP1 trigger production of?

A

type 1 interferons

38
Q

what are the PRR in the cytoplasm called?

A

RIG-I-like receptors

39
Q

what is the structure of RIG-I-like receptors?

A

Multidomain proteins
RNA helices domains

40
Q

What are 2 common RIG-I-like receptors?

A

RIG-1
MDAS

41
Q

what do RIG-I-like receptors detect?

A

dsRNA and 5’triphosphate ssRNA

42
Q

what is the function of CARD domains in RIG-I-like receptors?

A

recognition of viral RNA during viral replication
recognition of viral RNA modifications

43
Q

What is MAVS?

A

Mitochondrial antiviral sensing molecule
also contains a CARD domain

44
Q

how do RIG-I-like receptors trigger a signalling cascade?

A

the activated RIG-I-like receptor CARD domain recognises the CARD domain on the MAVS and triggers the same signalling cascade as TLRs

45
Q

what does cGAS recognise?

A

viral dsDNA

46
Q

how does cGAS recognise RNA viruses?

A

RNA viruses cause mitochondrial and nuclear damage so host DNA leaks into the cytoplasm and it shouldn’t be there so cGAS reacts to it

47
Q

what is the cGAS signalling pathway?

A
  1. active cGAS produces cGAMP using GTP and ATP
  2. cGAMP binds to STING to activate it
  3. STING moves to the Golgi and activates TBK1
  4. leads to IRF3 and NF-kB signalling
  5. activation of type 1 IFN
48
Q

what does cGAS stand for?

A

cyclic GMP-AMP synthetase

49
Q

in most cells what is interferon induction?

A

Biphasic

50
Q

how does biphasic interferon expression work?

A
  1. NF-kB and IRF3 activate IFNb
  2. IFNb signalling in the second phase causes IRF7 induction to activate IFNa
51
Q

how does interferon induction happen in dendritic cells?

A

IRF7 is constitutively expressed primed for virus infection
once contact with viral components IFNa is produced a lot quicker

52
Q

what is the interferon receptor?

A

IFNR - 2 domains
on the surface of most nucleated cells

53
Q

what is the interferon signalling cascade?

A
  1. interferons bind and activate the receptor
  2. tyrosine kinases Jak1 and Tyk2 phosphorylate themselves and then phosphorylate STAT proteins
  3. STAT1 and STAT2 bind Irf9 to make interferon stimulated gene factor (Isgf3)
  4. Isgf3 enters the nucleus and binds the interferon stimulated response element on the DNA
  5. induction of transcription of around 300 genes
54
Q

what are the 3 types of mechanisms involved in the antiviral state?

A
  1. to prevent viral replication
  2. to kill the infected cells
  3. to kill uninfected cells in the vicinity of infection
55
Q

how can the antiviral state be dangerous?

A

the killing of too many uninfected cells can cause serious damage especially in the brain or the liver

56
Q

what stages of the viral lifecycle can IFN stimulated proteins block?

A

entry
uncoating
RNA degradation
translation
virions leaving the cell

57
Q

what causes most of the initial viral symptoms?

A

the IFN response
(aches, fatigue, fever)

58
Q

what are the 3 classical antiviral mechanisms?

A
  1. PKR pathway to inhibit protein synthesis
  2. 2-5A system causes RNA cleavage
  3. the Mx pathway causes transcription inhibition
59
Q

what is PKR?

A

dsRNA-dependant protein kinase
- a serine-threonine protein kinase
N-terminal regulatory domain
C-terminal catalytic domain

60
Q

what happens to PKR when the interferon response is active?

A

levels in the cell increase 10-fold

61
Q

how is PKR made?

A

as inactive precursors to prevent host cell damage

62
Q

How is PKR activated?

A

activation after contact with dsRNA
autophosphorylation
activation of PKR

63
Q

how does PKR inhibit translation?

A

elongation factor 2 is phosphorylated by PKR so it cannot bind the ribosome so the ribosome cannot be active.
shuts down translation

64
Q

what is RNase L?

A

a nuclease that can degrade most cellular and viral RNA
remains inactive unless a second enzyme OAS is made

65
Q

what is OAS?

A

2’-5’ oligo(A) synthetase
makes oligomers of adenylic acid when activated by dsRNA
this then induces formation of active RNase L to induce apoptosis

66
Q

OAS1 in the interferon response

A

produced in high amount by the IFN response
makes small poly A segments to activate RNase L which degrade viral RNA

67
Q

what is one function of MxA?

A

Associates with the ER membrane to trap viral particles when the enter the cell
more specific binding so doesn’t block all viruses

68
Q

what are Mx proteins?

A

encoded by 2 genes mxA and mxB which produce MxA and MxB
reside in the cytoplasm
prevent viral replication but differently for each virus
more specific than PKR and RNase L

69
Q

why can viruses block the antiviral response?

A

viruses evolve more rapidly than our cells so they can adapt ways to overcome the IFN response

70
Q

how can Paramyxovirus prevent IFN production?

A

it makes proteins to block the initial sensing of the virus by blocking MDA5 and MAVS
or destroy intermediate sensing molecules

71
Q

how does Hepatitis C block the IFN response?

A

stops the formation of ISGF3 and STAT to block signalling and induction of ISG
also block PKR

72
Q

how does influenza block the IFN response?

A

protein NS1 binds to dsRNA to prevent PKR and RNase L/OAS system
directly binds PKR to prevent phosphorylation of elongation factor 2

73
Q

how much of the IFN response can viruses overcome?

A

pretty much all of it
more virulent viruses can block the IFN response
more susceptible patients could have specific IFN mutations to diminish the IFM response

74
Q

what can chronic IFN activation cause?

A

large physiological side effects and cell damage due to the firebreak effect killing uninfected cells

75
Q

Could interferons have therapeutic uses?

A

yes the firebreak effects could be useful for persistent infections but not transient infections

Infection and immunity (22 decks)

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