Interferon Flashcards

1
Q

What is interferon?

A

Transferrable factor produced when the cells are exposed to virus- like a danger signal

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2
Q

What is the effect of interferon binding to interferon receptors on cells?

A

It binds to specific receptors and signals the de novo transcription of hundreds of interferon stimulated genes (ISG)

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3
Q

What is the first interferon to be produced in a viral infection?

A

IFN beta

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4
Q

Which organ is IFN lambda very important in?

A

Liver

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5
Q

How does the innate immune system recognise non-self?

A

PRRs (pattern recognition receptors) on innate immune cells recognise
PAMPs (pathogen-associated molecular patterns)
NOTE: they often sense nucleic acids

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6
Q

Name two receptors that are involved in detecting the presence of viruses and state where they are found.

A

RIG-I like receptor (RLRs) – cytoplasmic

Toll-like receptors (TLRs) – plasma membrane + endosomal membrane

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7
Q

Describe RIG-I signalling.

A

RIG-I like receptors will recognise single stranded RNA in the cytoplasm of the cell and it will signal through MAVS (mitochondrial)
This will signal further downstream, leading to generation of IFN-beta transcripts

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8
Q

Describe TLR signalling.

A

TLR detects nucleic acids in the endosome (this isn’t normal)
It will signal to molecules outside the endosome (MyD88) and send various transcription factors to the nucleus
It will result in the switching on of expression of IFN alpha

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9
Q

Describe DNA sensing.

A

Mainly done by cGAS
This is an enzyme that binds to dsDNA in the cytoplasm and synthesises cGAMP (second messenger)
cGAMP diffuses to STING (found on endoplasmic reticulum)
This triggers phosphorylation of the same sets of transcription factors and signalling molecules the RNA viruses were triggering

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10
Q

Describe the structure of IFN receptors for IFN alpha and IFN beta

A

They are heterodimers of IFNAR 1 and IFNAR 2

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11
Q

What are Mx1 and Mx2?

A

GTPases with a homology to dynamin
Mx can form multimers that wrap around nucleocapsids of incoming viruses – this nullifies the viral genomes
Mx1 – inhibits influenza
Mx2 – inhibits HIV

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12
Q

When is PKR activated by cells?

A

It is an extreme measure and a last resort – only activated when the cell has no other option

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13
Q

Name a family of genes that suppress the cytokine signalling and turn off the response.

A

SOCS

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14
Q

State some mechanisms of viral evasion of the IFN response.

A

Avoid detection by hiding the PAMP
Interfere globally with host cell gene expression and/or protein synthesis
Block IFN induction cascades
Inhibit IFN signalling
Activate SOCS
Replication strategy that is insensitive to IFN

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15
Q

Explain how hepatitis C controls the interferon response.

A

NS3/4
This is a protease that cleaves MAVS
MAVS is important in detecting Hep C through the RIG-I pathway
So Hep C is not detected

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16
Q

Explain how influenza controls the interferon response.

A

NS1
Acts an antagonist to interferon induction by binding to the RIG-I/TRIM25/RNA complex and preventing activation of the signalling pathway
It also prevents nuclear processing of newly induced genes
NS1 also migrates to the nucleus where it prevents the export of newly synthesised genes

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17
Q

What do Pox viruses encode that helps deal with the interferonresponse?

A

They encode soluble cytokine receptors that mop up IFN and prevent it from reaching its receptors

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18
Q

Describe a potential therapeutic use of this feature

A

This could be useful in autoimmune or inflammatory conditions where IFN and other cytokines are produced in abundance

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19
Q

What are two proteins produced by Ebola virus that are particularly important in dealing with the immune response?

A

VP35

VP24

20
Q

What do these proteins do?

A

VP35 – inhibits the RIG-I pathway
VP24 – stops the signal getting through from the IFN beta receptor to the nucleus (stops the STAT1 molecule from getting to the nucleus)

21
Q

Describe how viral infections can cause cytokine storm.

A

Lots of virus propagation –> lots of interferon being produced –> massive release of TNF alpha and other cytokines

22
Q

What is a serious consequence of cytokine storm?

A

Pulmonary fibrosis – due to accumulation of immune cells in the lungs

23
Q

Explain why viruses that cannot control the interferon can beused as the next generation of live attenuated vaccines.

A

They will be able to infect the cells and it will replicate sufficiently to be able to mount an immune response but it wont replicate to the extent where it causes disease

24
Q

Explain why interferons are not frequently used as an antiviral therapy.

A

They stimulate the production of several cytokines and this causes several unpleasant side effects

25
Q

What disease is IFN used to treat?

A

Hepatitis C (a combination of pegylated IFN is used with ribavirin

26
Q

Explain the reasoning behind using IFN-lambda as a treatment for influenza.

A

Receptors for IFN lambda are only found on epithelial surfaces (the site of infection of influenza is respiratory epithelium)
IFN lambda cannot signal through immune cells and cause immunopathology
It will only induce an antiviral state in the epithelial cells

27
Q

Common intrinsic defense against virus

A

Viruses have a large ratio of C then G in their genome compared to humans. ZAP protein can recognise this in RNA and will result in degradation of this foreign RNA by an RNA exosome

28
Q

3 functions of type 1 interferons- these are produced first

A

Induce antimirobial state in infected and neighbouring cells
Modulate innate response to promote NK cells
Activate adaptive immune response

29
Q

What are the type 1 IFNs

A

IFN alpha and beta

30
Q

What cells secrete IFN beta

A

All cells

31
Q

What cells produce IFN alpha

A

Just plasmacytoid dendritic cells

32
Q

Transcription factor for IFN beta production induction

A

IRF-3

33
Q

Transcription factor for IFN alpha production induction

A

IRF-7

34
Q

Difference in genes for IFN alpha and beta

A

1 for beta

14 for alpha

35
Q

What receptor do type 1 IFN bind to

A

IFNAR which is on all cells

36
Q

What is type 2 IFN

A

IFN gamma

37
Q

Which cells produce type 2 IFN

A

T cells

NK cells

38
Q

Receptor for type 2 interferons

A

IFNGR

39
Q

What is type 3 IFN

A

Lamda

40
Q

Receptors for type 3 IFN

A

IL28R
IL10 beta
Found on epithelial cells

41
Q

How do we differentiate self from non self

A

PAMPs- for example DNA in cytoplasm which are detected by Pattern Recongntion Receptors

42
Q

Examples of cytoplasmic PRRs

A

RLRs

TLRs

43
Q

Way of detecting DNA in cytoplasm

A

cGAS

44
Q

How does cGAS work

A

If binds to DNA in cytoplasm enzyme is switched on producing cGAMP that binds toSTING protein on ER membrane- this acts as signalling

45
Q

What happens once PRRs have been activated

A

Production of IFN BETA that is soluble cytokine

46
Q

Common inborn genetic errors leading to lack of interferon production

A

IRF 7- lack of IFN alpha
IFNAR
IRF

47
Q

Examples of interferon stimulated genes

A

Proerin kinase A that inhibits translation
Serpine activates protein
ADAR induces errors in viral replication
IFITM3 restricts virus entry via endosomes