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Microbiology > Interferon > Flashcards

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 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
  1. Induce antimicrobial state in infected and neighbouring cells
  2. Modulate innate immune response to promote antigen presentation and NK cells but inhibit proinflammation
  3. 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 production induced 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 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 of genes

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 IFN2’s 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

IL-28 receptors

IL-10 beta receptors

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18
Q

Where are these type III IFN 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
  1. PRRs (pattern recognition receptors) on innate immune cells often sense nucleic acids (include RLR, TLR, NLR)
  2. PAMPs (pathogen-associated molecular patterns)
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21
Q

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

A
  1. RIG-I like receptor (RLRs) – cytoplasmic
  2. Toll-like receptors (TLRs) – plasma membrane + endosomal membrane
  3. NOD like receptors (NLR’s)- cytoplasmic
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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 antiviral-signaling protein)
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 that the cytoplasmic PAMP dsRNA causes

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 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
Q

What is IFITM3?

A

Interferon-induced transmembrane protein 3
On the membrane of endosomes, in cells that have been previously stimulated by IFN.
Restricts virus entry through endoscopes so the virus is broken down by acidic pH

NOTE: mice and people lacking IFITM3 get more severe influenza

28
Q

What are Mx1 and Mx2 and what are their functions?

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 (Suppressor of cytokine signalling)
note: IFN response only maintained for a few hours
subsequently ability to respond to IFN is lost due to negative regulation by SOCS genes to turn off IFN response
so antiviral state does not last

32
Q

State some mechanisms of viral evasion of the IFN response.

A

HIBIBAR

  1. Virus hides the PAMPS e.g inside vesicle
  2. Interfere with host cell gene expression and/or protein synthesis
  3. Block IFN induction cascades
  4. Inhibit IFN signalling
  5. Block action of individual IFN-induced antiviral enzymes
  6. Activate SOCS
  7. Replication that is insensitive to IFN
33
Q

Explain the mechanism of viral evasion in Hepatitis C

how it controls interferon response

A

NS3/4 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 the mechanism of viral evasion in Influenza

how it controls 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

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 interferon response?

A
  1. They encode soluble cytokine receptors (vaccinia virus B18) that mop up IFN and prevent it from reaching its receptors
  2. Also half their genome is comprised of accessory genes that can modify immune responses
37
Q

Describe a potential therapeutic use of this feature of Pox viruses

A

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

38
Q

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

A

VP35
VP24
VP30

39
Q

What do these proteins produced by the Ebola virus 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)
VP30- blocks RNAi expression

40
Q

What two techniques can be used to observe the skewing of the immune response by viruses?

A

Transcriptomimics – shows changes in mRNA production

Proteomimics – shows changes in protein expression

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
note: 100x more IFN is required for IL-6 induction (causes fever) than for Mx induction, thus more IFN stimulates a more serious response (up to cytokine storm)

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 be used 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 these 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

When would you see IFN gamma being expressed?

A
  1. Liver infections

2. Respiratory tract infections

50
Q

What are polymorphisms in IFN gamma associated with?

A

Improved outcomes from HCV and HBV with both spontaneous clearance and response to antiviral therapy

51
Q

What is the function of RLR’s?

A

Bind to MAVS (mitochondrial antiviral signalling protein) found on mitochondria and stimulate IFN-B production

52
Q

What is the function of TLR’s?

A

Make IFN-A

53
Q

Why is it the healthier you get (less ill) the more severe the clinical outcome?

A

Better at producing IFN

typical in Dengue haemorhaggic fever, Ebola and severe influenza

Microbiology (8 decks)

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