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Flashcards in Interferon Deck (51)
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1

What is the most common cause of sporadic encephalitis worldwide?

Herpes simplex encephalitis

2

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

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

3

What is interferon?

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

4

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

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

5

What are the three functions of type I interferons?

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

6

What are the type I interferons?

IFN alpha and IFN beta

7

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

IFN beta

8

Which cells produce IFN beta?

All cells produce IFN beta and all tissues have IFNAR receptors

9

What is IFN beta induction triggered by?

IRF-3

10

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

Plasmacytoid dendritic cells

11

What do Plasmacytoid dendritic cells express high levels of?

IRF-7

12

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

Alpha – 13/14 isotypes Beta – ONE

13

Which IFN comes under type II interferon?

IFN-gamma - specialist immune signalling molecule

14

Which cell types produce type II IFN?

Produced by activated T cells and NK cells

15

Which receptor do these type II IFN signal through?

IFNGR

16

Which IFN falls under type III IFN?

IFN-lambda

17

Which receptors do type III IFNs signal through?

IL-28 receptors IL-10 beta receptors

18

Where are the receptors for type III inteferons mainly present?

Epithelial surfaces E.g. respiratory epithelium and gut

19

Which organ is IFN lambda very important in?

Liver

20

How does the innate immune system recognise non-self?

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

21

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

RIG-I like receptor (RLRs) – cytoplasmic Toll-like receptors (TLRs) – plasma membrane + endosomal membrane Both examples of PRRs

22

Describe RIG-I signalling.

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

Describe TLR signalling.

  • 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

Describe DNA sensing.

  • 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

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
  • 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

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.

Inhibits translation

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 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

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 (pox way of dealing with interferon)

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 ebola proteins do?

  • VP35 – inhibits the RIG-I pathway
  • VP24 – inhibits interferon signalling to the nucleus

40

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

41

What is a serious consequence of cytokine storm?

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

42

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

43

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

44

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

45

What disease is IFN used to treat?

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

46

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

47

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

48

What is the role of ZAP?

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

49

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

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

50

What kind of cells secrete interferon beta?

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

51

Breifly describe 6 genes stimulated by inteferons

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