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MCD Microbiology > Interferons > Flashcards

Interferons Flashcards

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1
Q

what effect does interferon production have on the body?

A

fever

feeling of being unwell

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2
Q

what do interferons stimulate overall?

A

they signal the transcription of Interferon Stimulated Genes in the infected cell and neighbouring cells

e.g. IFITM3

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3
Q

what are the 3 functions of type 1 interferons?

A

o Induce antimicrobial state (local and adjacent).

o Modulate innate response by acting as an adjuvant
– promote Ag presentation (and NK) but inhibit pro-inflammation.

o Activate adaptive immune response.

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4
Q

name a type 1 IFN

A

IFN alpha, beta , kappa etc
- these can be made by all cells
- all cells can respond to these
focus on beta

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5
Q

what gene leads to the production of IFN beta?

A

single gene: IRF-3

interferon regulatory factor

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6
Q

what gene leads to the production of IFN alpha?

A

IRF-7

IFN-alpha has 13/14 isotopes however

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7
Q

what interferon is secreted first in infection? what receptor do they bind to?

A

IFN beta binds to IFNAR on the same cell and neighbouring cells

infected cells secrete IFN

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8
Q

what cells secrete IFN- alpha?

A

Plasmacytoid dendritic cells and macrophages

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9
Q

what type of molecules are IRF?

A

transcription factors that cause transcription of their respective IFN cytokine

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10
Q

examples of type 2 and type 3 interferons

where are they produced?

A

type 2: IFN gamma
- made by immune cells

type 3: IFN lambda
- made by all cells but only acts on the epithelial cells

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11
Q

what cells produce type 2 IFN? what receptor do they bind to?

A

IFN gamma is produced by T cells and NK cells (i.e. immune cells)

receptor: IFNGR

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12
Q

which receptors do IFN lambda (type 3) signal through?

A

IL28R and IL10beta

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13
Q

what cells respond IFN lambda?

A

epithelial cells so normally expressed during resp tract infections and liver infections

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14
Q

what are the polymorphisms in IFN lambda associated with?

A

associated with improved outcomes from HCV and HBV with both spontaneous clearance and response to antiviral therapy.

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15
Q

how does the body differentiate self from non-self?

A

using PAMPS and PRR

  • PAMPs= Pathogen Associated Molecular Patterns
  • PRR= Pattern Recognition Receptor
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16
Q

give an example of a PAMP

A

dsRNA (foreign nucleic acids)

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17
Q

what are PRRs?

A

Pattern Recognition Receptors

– these sit inside cells and detect PAMPs.

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18
Q

give example of PRRs

A

o RLRs
– RIG-I-like Receptors (cytoplasmic).

o TLRs
– Toll-Like Receptors (endosomal).

o NLRs
– NOD (Nucleotide Oligomerisation Domain) Like Receptors (cytoplasmic).

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19
Q

where are RLRs (PRR) found? what does it stimulate?

A

Bind to Mavs (found on mitochondria) and stimulate signalling and IFN-beta production.

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20
Q

where are TLRs (PRR) found? what does it stimulate?

A

Found in endosomes and makes IFN alpha

TLR–> MyD88–> IFNalpha

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21
Q

which PRR leads to IFN beta production?

A

RIG-I-like receptors

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22
Q

what PRR leads to IFN alpha production?

A

Toll Like Receptor

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23
Q

what makes a piece of nuclei acid foreign? what will detect this?

A

e.g. mRNA without a polyA tail and Cap is recognised as foreign
this is detected by PRRs namely RLRs (RIG-I+MDA5+LGP2)

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24
Q

what happens when foreign nucleic acids are detected by RLRs?

A

ss/dsRNA binds leading to the stimulation of Mavs (found on mitochondrial membrane) to form a complex and trigger cascades that lead to IFN beta expression

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25
Q

what is the consequence of the cascades initiated by the recognition of nucleic acids by RLR?

A

a resulting kinase will phosphorylate IRF-3
this leads to its dimerisation so it can move into the nucleus as a transcription factor and bind to the promoter of IFN beta so transcription can occur

[RLR–> IRF-3–> IFN beta]

Nb TLR–> IRF-7–> IFN alpha

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26
Q

what is the overall pathway of IFN beta production?

A

nucleic acid–> RLR i.e. RIG-I–> IRF-3–> IFN beta

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27
Q

why is having TLRs important?

A

viruses can use endosomes to enter cells

28
Q

what is the consequence of nuclei acids binding to TLRs?

A

nucleic acid in endosome–> TLR–> MyD88–> IRF-7–> IFN alpha production by dendritic cells

29
Q

how are DNA viruses detected?

cGAS specific to dsDNA

A
  • cGAS enzyme becomes activated when bound to dsDNA in the cytoplasm
  • cGAMP production is promtoed via 2nd messenger pathways
  • cGAMP passed to STING protein (found on ER)
  • cascades initiated
  • IRF-3 phosphorylation
  • dimerisation
  • type 1 IFN production

[cGAS–> cGAMP–> STING–> IRF-3–> Type 1 IFN]

30
Q

what are IFN receptors when activated?

A

heterodimers of IFNAR1 and IFNAR2

31
Q

what enables IFN to have a paracrine effect?

A

IFN are soluble cytokines

32
Q

once a type 1 interferon (IFN alpha or beta) has been produced and released from the infected cell, how does it cause further transcription?

A
  • IFNa/b dimerises IFNAR1 and IFNAR2 on a neighbouring cell
  • the attached JAK1 and TYK2 cross phosphorylate
  • STAT proteins are activated
  • the activation of STATs leads to the production of different Interferon Stimulated Genes required for 3 different responses
33
Q

what are the types of responses that STAT activation, leading to ISG transcription, activates?

A

1) Antiviral response (ISRE).
2) Inflammatory response (GAS).
3) Repressors of the inflammatory pathways (GAS

34
Q

what is the effect of interferon inducing transcription of ISGs?

A

induce transcription of HUNDREDS of antiviral mediators – hence why you get a fever and feel sick.

35
Q

what are examples of genes stimulated for transcription by interferon? what are some of their functions

A

PKR, Mx, IFITM3, miRNAs, ADAR, apoptosis, cell cycle arrest, etc.

  • PKR–>
    inhibits translation function of ribosomes (which viruses are dependent on from the host)
  • Mx–>
    inhibits incoming viral genomes
  • IFITM3–>
    restricts the entry of viruses via endosomes by locking them within
  • Tetherin–>
    prevent budding of many enveloped viruses
36
Q

What is the function of the ISG IFITM3?

A

Interferon Induced Transmembrane Protein 3:

Restricts virus entry through endosomes by stopping them escaping so the virus is broken down by the acidic pH.

A variant (with defect) can affect the outcome of an influenza infection

37
Q

what is the function of the ISG Mx (Mx1 and Mx2)?

A

inhibit viral genomes:
GTPases with a homology to dynamin forms multimers to wrap around nucleocapsids of viruses.

Mx1 – inhibits influenza.
Mx2 – inhibits HIV.

38
Q

what is the importance of switching off the IFN response? how is it switched off?

A

IFN response cannot last (maintained for a few hours) as it causes the feeling of sickness

the ability to respond to IFN is lost gradually due to negative regulation

39
Q

what turns off the IFN response?

A

SOCS

(Suppressor of Cytokine Signalling) genes

40
Q

how do viruses evade the IFN response?

A 
o H 	
Virus hides the PAMPS
 – e.g. inside vesicles.
o A	
Activate SOCS prematurely 
o B	
Block IFN induction cascades.					
o I	
Inhibit IFN signalling directly 					
o B	
Block action of individual IFN-induced antiviral enzymes.
o I	
Interference with host cell gene expression (or protein synthesis).

o R
Replication that is insensitive to IFN (within membrane bound compartment)

41
Q

how has influenza evolved to evade the IFN response?

A

NS1 protein inhibits IFN signalling [upstream] by binding to RIG-1/TRIM25/RNA complex (RLR)

this prevents activation of signalling pathway and prevents nuclear processing of newly induced genes.

42
Q

how has HCV (Hep C) evolved to evade the IFN response?

A

Mavs cleavage

NS3/4 protease block IFN induction cascades [downstream] by cleaving Mavs so no IFN is produced

43
Q

how has the POX (and herpes) virus evolved to evade the IFN response?

A

DNa viruses have enough space in their genome to encode for accessory genes (actually makes up half their genome) that produce proteins that modify the host immune response

e.g. encode soluble cytokine receptors (vaccinia virus B18)

44
Q

how does the POX viruse’s evasion technique of IFN response help with therapeutics

A

Pox viruses encode soluble cytokine receptors (vaccinia virus B18) that have future immune therapies potential as their deletion can be used for attenuated vaccines

45
Q

how has the Ebola virus evolved to evade the IFN response?

A

avoids detection; prevents ISG expression in other cells via the use of VP proteins :

VP35
– blocks RIG-I Like complexes and RNAi expression.

VP30
– blocks RNAi expression.

VP24
– directly blocks IFN signalling.

46
Q

how can IFN be harmful to the body?

A

for example 100x more IFN is required for IL-6 induction (causes fever) than for Mx induction. Therefore more IFN stimulates a more severe response (up to a cytokine storm

47
Q

what is a cytokine storm?

A

virus replication induces high IFN accompanied by a massive surge in TNFa, IL-6 and others.

This recruits immune cells that release more cytokines

48
Q

what is the paradoxical outcome of having a cytokine storm?

consider age

A

Differences in the clinical outcome may vary with age and health but the healthier you are, paradoxically, the more severe the clinical outcome as you’re better at producing IFN.

49
Q

what diseases may cause a cytokine storm?

A

Dengue haemorrhagic fever
Ebola
Severe influenza

50
Q

what are the cytokines involved in a cytokine storm? what is the result of the release of these cytokines?

A 
TNFa
IFNa/b
IFNg
IL-1
IL-6
CCL2

Result in endothelial dysfunction (become leaky), inflammatory responses and pulmonary fibrosis.

51
Q

what makes live attenuated vaccines effective in their manufacture?

A

viruses deficient in control of IFN are attenuated in IFN competent cells
Cells naturally or engineered to be deficient in IFN response can be used to grow these attenuated virus strains.

52
Q

what is the effect of using a live attenuated vaccine?

A

high IFN levels:

they induce and recruit useful immune cells with IFN acting as an adjuvant

53
Q

what was the advantage of using IFN lambda as therapeutic drug for influenza?

A

specific to epithelial cells:
IFN lambda only stimulates an anti-viral state and
NOT an immune response and immunopathology as only epithelial cells are involved and immune cells are not recruited

54
Q

what is the basis for the consideration of using IFN in cancer treatment?

A

Cancer cells may be deficient in IFN and so if a cancer patient is given an oncolytic novel virus, the virus takes advantage and can kill the cancer cells whilst the healthy cells produce interferon to combat the virus.

55
Q

what disease can herpes simplex cause?

A

common cause of sporadic encephalitis in western world (common in childhood)

impaired CNS intrinsic IFN response

56
Q

what are the inborn genetic errors that lead to herpes simplex encephalitis?

A

TLR3, UNC93B1, TRIF, TRAF3, TBK1, IRF3

impaired CNS intrinsic IFN response leading to HSE

(Normally those with HSV infection have a working IFN response)

57
Q

how does the epithelial barrier (entry point for viruses) fool the virus?

A

using decoy receptors called collectin

58
Q

how is collectin overcome by influenza?

A

neuramidase enzymatically removes decoy collectin receptors so gain access to the “real” receptors to get into the cell

59
Q

how does TLR and RIG-1 differ?

A

TLR is on the cell surface

RIG-1 is intracellular

60
Q

PAMPs

A

unusual/ non self nucleic acids recognised by PRRs

61
Q

where does newly produced IFN by the infected cell go?

A

to receptors

  • of the infected cell itself
  • on neighbouring cells

leads to synthesis of other antiviral genes

62
Q

how does HCV evade IFN response?

A

targets and destroys MAVS (protein in the detection pathway)

63
Q

how does influenza A virus evade IFN response?

A

NS1 protein binds to RIG-1 ( intracellular PRR)

stops is seeing the PAMP

64
Q

how do poxviruses evade the IFN response?

A

secrete soluble cytokine receptors (vaccinia virus B18)

this mops up cytokines so stop it reaching its own receptors

65
Q

what sort of IFN is used in in Hep C treatment?

A

peginterferon alpha

MCD Microbiology (6 decks)

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