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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

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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
what does TLR3 recognise?
dsRNA
26
what does TLR7/8 recognise?
viral ssRNA
27
what does TLR9 recognise?
Hypomethylated CpG DNA
28
where is TLR3 expressed?
Macrophages dendritic cells B cells intestinal epithelium
29
where is TLR4 expressed?
Macrophages dendritic cells Mast cells intestinal epithelium
30
what does TLR4 recognise?
specific viral proteins
31
where is TLR7 expressed?
macrophages B cells plasmacytoid dendritic cells
32
where is TLR8 expressed?
macrophage neutrophils
33
where is TLR9 expressed?
macrophage plasmacytoid dendritic cells B cells NK cells microglial cells
34
how can a virus trigger TLR3 in the endosome?
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
what is the signalling cascade for TLR3 and TLR4 sensing?
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
what type of cytokines do NF-kB and AP1 trigger production of?
general pro inflammatory cytokines
37
what type of cytokines do NF-kB, IRF3 and AP1 trigger production of?
type 1 interferons
38
what are the PRR in the cytoplasm called?
RIG-I-like receptors
39
what is the structure of RIG-I-like receptors?
Multidomain proteins RNA helices domains
40
What are 2 common RIG-I-like receptors?
RIG-1 MDAS
41
what do RIG-I-like receptors detect?
dsRNA and 5'triphosphate ssRNA
42
what is the function of CARD domains in RIG-I-like receptors?
recognition of viral RNA during viral replication recognition of viral RNA modifications
43
What is MAVS?
Mitochondrial antiviral sensing molecule also contains a CARD domain
44
how do RIG-I-like receptors trigger a signalling cascade?
the activated RIG-I-like receptor CARD domain recognises the CARD domain on the MAVS and triggers the same signalling cascade as TLRs
45
what does cGAS recognise?
viral dsDNA
46
how does cGAS recognise RNA viruses?
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
what is the cGAS signalling pathway?
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
what does cGAS stand for?
cyclic GMP-AMP synthetase
49
in most cells what is interferon induction?
Biphasic
50
how does biphasic interferon expression work?
1. NF-kB and IRF3 activate IFNb 2. IFNb signalling in the second phase causes IRF7 induction to activate IFNa
51
how does interferon induction happen in dendritic cells?
IRF7 is constitutively expressed primed for virus infection once contact with viral components IFNa is produced a lot quicker
52
what is the interferon receptor?
IFNR - 2 domains on the surface of most nucleated cells
53
what is the interferon signalling cascade?
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
what are the 3 types of mechanisms involved in the antiviral state?
1. to prevent viral replication 2. to kill the infected cells 3. to kill uninfected cells in the vicinity of infection
55
how can the antiviral state be dangerous?
the killing of too many uninfected cells can cause serious damage especially in the brain or the liver
56
what stages of the viral lifecycle can IFN stimulated proteins block?
entry uncoating RNA degradation translation virions leaving the cell
57
what causes most of the initial viral symptoms?
the IFN response (aches, fatigue, fever)
58
what are the 3 classical antiviral mechanisms?
1. PKR pathway to inhibit protein synthesis 2. 2-5A system causes RNA cleavage 3. the Mx pathway causes transcription inhibition
59
what is PKR?
dsRNA-dependant protein kinase - a serine-threonine protein kinase N-terminal regulatory domain C-terminal catalytic domain
60
what happens to PKR when the interferon response is active?
levels in the cell increase 10-fold
61
how is PKR made?
as inactive precursors to prevent host cell damage
62
How is PKR activated?
activation after contact with dsRNA autophosphorylation activation of PKR
63
how does PKR inhibit translation?
elongation factor 2 is phosphorylated by PKR so it cannot bind the ribosome so the ribosome cannot be active. shuts down translation
64
what is RNase L?
a nuclease that can degrade most cellular and viral RNA remains inactive unless a second enzyme OAS is made
65
what is OAS?
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
OAS1 in the interferon response
produced in high amount by the IFN response makes small poly A segments to activate RNase L which degrade viral RNA
67
what is one function of MxA?
Associates with the ER membrane to trap viral particles when the enter the cell more specific binding so doesn't block all viruses
68
what are Mx proteins?
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
why can viruses block the antiviral response?
viruses evolve more rapidly than our cells so they can adapt ways to overcome the IFN response
70
how can Paramyxovirus prevent IFN production?
it makes proteins to block the initial sensing of the virus by blocking MDA5 and MAVS or destroy intermediate sensing molecules
71
how does Hepatitis C block the IFN response?
stops the formation of ISGF3 and STAT to block signalling and induction of ISG also block PKR
72
how does influenza block the IFN response?
protein NS1 binds to dsRNA to prevent PKR and RNase L/OAS system directly binds PKR to prevent phosphorylation of elongation factor 2
73
how much of the IFN response can viruses overcome?
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
what can chronic IFN activation cause?
large physiological side effects and cell damage due to the firebreak effect killing uninfected cells
75
Could interferons have therapeutic uses?
yes the firebreak effects could be useful for persistent infections but not transient infections

Infection and immunity (22 decks)

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