Interferon Flashcards

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1
Q

What is the most common cause of sporadic encephalitis worldwide?

A

Herpes simplex encephalitis

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2
Q

Which subset of the population is herpes encephalitis most common in?

A

Most common in childhood – affecting previously healthy individuals on primary infection with HSV-1

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3
Q

What is interferon?

A

Transferrable polypeptide factor produced and secreted from cells when the cells are exposed to virus

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4
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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5
Q

What are the three functions of type I interferons?

A

Induce antimicrobial state in infected and neighbouring cells

Modulate innate immune response to promote antigen presentation and NK cells but inhibit proinflammation

Activate the adaptive immune response

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6
Q

What are the type I interferons?

A

IFN alpha and IFN beta

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7
Q

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

A

IFN beta

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8
Q

Which cells produce IFN beta?

A

All cells produce IFN beta and all tissues have IFNAR receptors

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9
Q

What is IFN beta induction triggered by?

A

IRF-3

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10
Q

Name a cell type that is specialised for producing IFN alpha.

A

Plasmacytoid dendritic cells

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11
Q

What do Plasmacytoid dendritic cells express high levels of?

A

IRF-7

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12
Q

How many genes are there for IFN alpha and IFN beta?

A

Alpha – 13/14 isotypes

Beta – ONE

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13
Q

Which IFN comes under type II interferon?

A

IFN-gamma - specialist immune signalling molecule

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14
Q

Which cell types produce this IFN?

A

Produced by activated T cells and NK cells

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15
Q

Which receptor do these IFNs signal through?

A

IFNGR

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16
Q

Which IFN falls under type III IFN?

A

IFN-lambda

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17
Q

Which receptors do type III IFNs signal through?

A

L-28 receptors

IL-10 beta receptors

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18
Q

Where are the receptors for type III inteferons mainly present?

A

Epithelial surfaces

E.g. respiratory epithelium and gut

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19
Q

Which organ is IFN lambda very important in?

A

Liver

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20
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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21
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

Both examples of PRRs

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22
Q

Describe RIG-I signalling.

A

RIG-I like receptors will recognise single stranded RNA in the cytoplasm of the cell

It will signal through MAVS (mitochondrial)

This will signal further downstream, leading to phosphorylation of IRF3 and IRF7

Theses will dimerise and enter the nucleus to act as a transcription factor

Leads to the generation of IFN-beta transcripts

Note:
Mavs may also activate pathways leading to NFkB activation or Jun kinase activation

23
Q

Describe TLR signalling.

A

TLR detects nucleic acids in the endosome (this isn’t normal) or outside the cell

It will signal to one of 2 molecules outside the endosome MyD88 or Trif

Trif activates IRF3

Myd88 activates NFkB and IRF7

It will result in the switching on of expression of INF alpha and beta

24
Q

Describe DNA sensing.

A

Mainly done by cGAS

This is an enzyme that binds to dsDNA in the cytoplasm

Then synthesises cGAMP (second messenger)

cGAMP diffuses to STING (found on endoplasmic reticulum)

This triggers phosphorylation of IRF-3 which then dimerises and acts as a transcription factor

25
Q

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

A

They are heterodimers of IFNAR 1 and IFNAR 2

26
Q

Describe the signalling from IFNAR receptors

A

IFN binds and the IFN receptor activates JAK

This phosphorylates the STAT molecules

STAT molecules dimerise and combine with IRF-9

It then goes to the nucleus, binds to a promoter and regulates transcription

27
Q

What is IFITM3?

A

Interferon-induced transmembrane protein 3

These sit on the membrane of endosomes, in cells that have been previously stimulated by IFN

It prevents fusion of the virus membrane with the endosomal membrane so the virus gets trapped in the endosome

NOTE: mice and people lacking IFITM3 get more severe influenza

28
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

29
Q

Describe the actions of Protein Kinase R.

A

It phosphorylates the alpha subunit of eIF2 (initiation factor) that is important in translation

This prevents ribosomes from binding to mRNA so NO NEW GENES WILL BE TRANSLATED

It also phosphorylates NFkB, which is an important transcription factor that is part of the interferon and inflammatory response

30
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

31
Q

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

A

SOCS

32
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

33
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

34
Q

Explain how influenza controls the interferon response.

A

NS1 protein

Acts an antagonist to interferon induction by binding to the RIG-I/TRIM25/RNA complex and preventing activation of the Mavs signalling pathway

NS1 also migrates to the nucleus where it prevents the export of newly synthesised genes e.g. IFN beta genes and ISGs in neighboring cells

35
Q

What type of virus are Pox and Herpes viruses?

A

Large DNA viruses

36
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

37
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

38
Q

Name two proteins produced by HIV that helps deal with restriction factors and state what they target.

A

Vif – APOBEC

Vpu – Tetherin

39
Q

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

A

VP35

VP24

40
Q

What do these proteins do?

A

VP35 – inhibits the RIG-I pathway

VP24 – stops the signal getting through from the IFN receptors to the nucleus

41
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

42
Q

What is a serious consequence of cytokine storm?

A

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

43
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

44
Q

The downside of this feature of the viruses is that these virus particles can’t be propagated in normal healthy cells. What is the solution to this issue?

A

Propagate the viruses in cells that are deficient in the IFN response

45
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

46
Q

What disease is IFN used to treat?

A

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

47
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

48
Q

Explain how oncolytic viruses would work.

A

Viruses are engineered that can uniquely replicate in tumour cells and kill them

Generally speaking, cancer cells are deficient in their ability to mount a proper interferon response

So, a virus that is unable to control the IFN response will NOT be able to replicate in normal healthy cells but they will be able to infect and replicate in cancer cells

49
Q

What is the pathway of virus to interferon production?

A
  1. Virus detected by TLR3
  2. TRAF 3
  3. TBK1
  4. IRF3
50
Q

What is the role of ZAP?

A

Protein that determins how likley a nucleic acid sequence is likley to belong to the host

Detects how many CpG sites there are

If there is lots then ZAP binds to the nucleic acid and targets it for degredation

51
Q

Does ZAP play much of a role in defence from human viruses?

A

No as human viruses have evolved to down regulate their CpG sites

However, non-human viruses haven’t so ZAP plays a key role in defence against these viruses

52
Q

What kind of cells secrete interferon beta?

A

Immune cells:
Macrophages
Dendritic cells
Plasmacytoid dendritic cells (pdcs)

53
Q

Breifly describe 6 genes stimulated by inteferons

A

PKR Protein Kinase R: inhibits translation

2’5’OAS: activates RNAse L that destroys ss RNA

Mx: inhibits incoming viral genomes

ADAR : induces errors during viral replication

Serpine: activates proteases

Viperin: inhibits viral budding