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Y2 MCD Microbiology Fwong > Interferon > Flashcards

Interferon Flashcards

1
Q

What is the most common cause of sporadic encephalitis worldwide?

A

Herpes simplex virus causing 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
Promote antigen presentation by APC cells
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

Which transcription factor triggers IFN beta induction?

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 IFN gamma?

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: PAMPS are often viral nucleic acids and PRR often detects these

21
Q

Name two types of PRRs 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

22
Q

Describe RIG-I signalling.

A

How RLRs work
ssRNA is foreign (a PAMP), likely from a virus
RigI binds to it and then signals Mavs (mitochondria antiviral signaling protein) which is on the mitochondrial membrane
Mavs signals various different downstream pathways that eventually lead to IRF3 and IRF7 phosphorylation within the cytoplasm (this is all you need to know)
IRF3 and IRF7 dimerise and enter nucleus to act as transcription factors by binding to promoter regions
Eg This leads to transcription of IFN beta gene which would lead to IFN Beta protein that travels to neighbouring cells and induces an antiviral state (by binding onto IFNAR receptors)

23
Q

Describe TLR signalling.

A

A lot of viruses enter via endosomes.
There are TLR receptors on the membrane of endosomes
Viral DNA (PAMP) is detected by TLRs
This triggers activation of IRF3 and IRF7 which act as transcription factors that enter the nucleus
This leads to transcription of Type 1 interferons like IFNalpha or beta.
These can leave the cell, bind to receptors on other neighbouring cells etc.

24
Q

Describe DNA sensing.

A

cGAS senses viral DNA in cytoplasm
cGAS synthesizes a dinucleotide called cGAMP
cGAMP is detected by a protein that sits on the membrane of rough ER called STING
STING gets phosphorylated which then causes the same thing as the defence against RNA viruses:
IRF3 is phosphorylated and activated
IRF3 is the transcription factor for production of interferons

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 pathway induced by binding of interferons to IFNAR receptors
IFN from adjacent cells bind to an interferon receptor (IFNAR) This triggers the jak-stat pathway This signaling pathway eventually leads to transcription of various anti-viral, interferon stimulated genes in adjacent cells
27
What is IFITM3?
Interferon-induced transmembrane protein 3 This is another ISG and Production of this protein is triggered by interferons and this protein sits in the endosomal membrane and stops virus from escaping endosomes. This protein is important in the defence against 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 Main point: inhibits translation. This is good against virus BUT it also means your host cell cant translate physiological proteins. This response is almost suicidal but it will stop the virus from spreading to nearby cells 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 (suppressor of cytokine signalling) genes are switched on towards the end of the interferon response and hence turn off the response.
32
State some mechanisms of viral evasion of the IFN response.
- Avoid detection by hiding the PAMP (so not detected by eg TLRs or RLRs) - Interfere globally with host cell gene expression and/or protein synthesis ie stop the host from expressing genes and proteins, and take that over and use it to produce their own proteins - Block IFN induction cascades: induction cascades are the signalling pathways that leda to production of IFN eg all the MAVS etc - Inhibit IFN signalling ie interferes with the process when IFN is released and acts on other receptors - Block the action of individual IFN induced antiviral enzymes - Activate SOCS genes early - Replication strategy that is insensitive to IFN ie divide so quickly that they spread to nearby cells before the original cell can even produce an interferon response
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
What are two proteins produced by Ebola virus that are particularly important in dealing with the immune response?
VP35 | VP24
39
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)
40
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
41
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
42
What is a serious consequence of cytokine storm?
Pulmonary fibrosis – due to accumulation of immune cells in the lungs
43
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
44
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
45
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 This is because IFNalpha/beta from the drug can bind to IFNAR which is present on all cells, including immune cells. This triggers an antiviral state in immune cells (good) BUT it also causes them to release proinflammatory cytokines and hence induces immunopathology
46
What disease is IFN used to treat?
Hepatitis C (a combination of pegylated IFN is used with ribavirin
47
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
48
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

Y2 MCD Microbiology Fwong (8 decks)

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