Interferon Flashcards

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 factor produced 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 these 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 these receptors 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

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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 and it will signal through MAVS (mitochondrial)
This will signal further downstream, leading to generation of IFN-beta transcripts

23
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

24
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

25
Describe the structure of IFN receptors for IFN alpha and IFN beta
They are heterodimers of IFNAR 1 and IFNAR 2
26
Describe the signalling from IFNAR receptors
IFN binds and the IFN receptor activates Jak and Tyk, which goes on to phosphorylate 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
What is IFITM3?
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
What are Mx1 and Mx2?
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
Describe the actions of Protein Kinase R.
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
When is PKR activated by cells?
It is an extreme measure and a last resort – only activated when the cell has no other option
31
Name a family of genes that suppress the cytokine signalling and turn off the response.
SOCS
32
State some mechanisms of viral evasion of the IFN response.
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
Explain how hepatitis C controls the interferon response.
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
Explain how influenza controls the interferon response.
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
35
What type of virus are Pox and Herpes viruses?
Large DNA viruses
36
What do Pox viruses encode that helps deal with the interferonresponse?
They encode soluble cytokine receptors that mop up IFN and prevent it from reaching its receptors
37
Describe a potential therapeutic use of this feature
This could be useful in autoimmune or inflammatory conditions where IFN and other cytokines are produced in abundance
38
Name two proteins produced by HIV that helps deal with restriction factors and state what they target.
Vif – APOBEC | Vpu – Tetherin
39
Describe the normal action of APOBEC.
APOBEC is involved in the innate immune resistance to retroviruses and hepadnaviruses APOBEC modifies some of the nucleotides in reverse transcription and makes them into the wrong version APOBEC deaminates dC to dU in the minus strand of viral cDNA during reverse transcription This leads to G to A hypermutation resulting in ERROR CATASTROPHE This results in so many mutations that the viral genome becomes nonsense and the virus can’t replicate
40
What is the effect of Vif on APOBEC?
Vif counteracts the activity of APOBEC and targets it for degradation This removes the interference of APOBEC with reverse transcription
41
Describe the normal action of tetherin.
Tetherin sits on the cell surface of infected cells and binds to viruses that try to escape the cell to go and infect other cells This limits the spread of viral infection
42
What is the effect of Vpu on tetherin?
Vpu pulls tetherin back from the cell surface and targets it for degradation
43
What are two proteins produced by Ebola virus that are particularly important in dealing with the immune response?
VP35 | VP24
44
What do these proteins do?
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)
45
What two techniques can be used to observe the skewing of the immune response by viruses?
Transcriptomimics – shows changes in mRNA production | Proteomimics – shows changes in protein expression
46
Describe how viral infections can cause cytokine storm.
Lots of virus propagation --> lots of interferon being produced --> massive release of TNF alpha and other cytokines
47
What is a serious consequence of cytokine storm?
Pulmonary fibrosis – due to accumulation of immune cells in the lungs
48
Explain why viruses that cannot control the interferon can beused as the next generation of live attenuated vaccines.
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
49
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?
Propagate the viruses in cells that are deficient in the IFN response
50
Explain why interferons are not frequently used as an antiviral therapy.
They stimulate the production of several cytokines and this causes several unpleasant side effects
51
What disease is IFN used to treat?
Hepatitis C (a combination of pegylated IFN is used with ribavirin
52
Explain the reasoning behind using IFN-lambda as a treatment for influenza.
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
53
Explain how oncolytic viruses would work.
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