Interferon Flashcards

1
Q

what is the most common cause of sporadic encephalitis in the western world?

A
  • herpes simplex encephalitis

- most common in childhood

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2
Q

what are the 6 genes that are implicated with inborn errors in HSE?

A
  • TLR3
  • UNC(3B1
  • TRIF
  • TRAF3
  • TBK1
  • IRF3
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3
Q

what do these gene errors do?

A
  • impairs CNS intrinsic interferon alpha/beta response to HS infection
  • virus replicated to a much higher extend than would be otherwise
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4
Q

what is interferon?

A

transferable factor produced when cells are exposed to virus

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5
Q

what does interferon do?

A
  • binds to specific receptors
  • signals activation of de novo transcription of hundreds of interferon stimulated genes
  • puts cell into an anti-viral state
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6
Q

what are type 1 interferons?

A

polypeptides secreted from infected cells

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7
Q

what are the 3 main functions of type 1 interferons?

A
  • induce antimicrobial state in infected and neighbouring cells
  • modulate innate response
  • promotes antigen presentation and NK cells
  • inhibits proinflammation
  • activate adaptive immune response
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8
Q

what is the first interferon to be made?

A
  • IFN beta
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9
Q

describe how type 1 interferons cause adaptive immune response

A
  • cells sense viral infection
  • make an interferon response
  • results in synthesis of new copies of IFN-beta
  • IFN beta can diffuse and interact w/ receptors on neighbouring cells
  • switches on genes in neighbouring cells switches them into anti-viral state
  • recruits APCs and adaptive immune cells
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10
Q

what are specialized cells that are good at making interferon?

A
  • plasmacytoid dendritic cells

- particularly IFN-alpha

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11
Q

what are the type 1 interferons? what are they secreted from?

A
  • IFN alpha/beta
  • IFN beta secreted by ALL cells
  • IFN beta induction triggered by IRF-3
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12
Q

where is the IFNAR receptor?

A

present on all tissues

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13
Q

how many genes are there for IFN alpha/beta?

A
  • one gene for IFN-beta

- 13/14 isotypes of IFN-alpha

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14
Q

what is type 2 interferon? What produces it?

A
  • much more specialist immune signalling molecule
  • produced by immune cells (activated cells, NK cells)
  • signals through IFNGR
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15
Q

what is type 3 interferon? where is it present?

A
  • IFN lambda

- mainly on epithelial cells

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16
Q

what does type 3 interferon signal through?

A
  • IL28 receptor

- IL10 beta

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17
Q

what does IFN lambda do?

A
  • protects barriers of your body e.g. resp epithelium, gut

- important in liver

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18
Q

what are polymorphisms in IFN lambda gene associated with?

A

different outcomes from liver viruses

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19
Q

how do you differentiate self from non self?

A
  • PAMPs
  • PRRs
  • often sense foreign nucleic acids
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20
Q

what are the receptors for sensing the presence of viruses?

A
  • RLRs (cytoplasmic RIG-1 like receptors)
  • TLRs (endosomal toll like receptors)
  • cytoplasmic nucleotide oligomerisation domain receptors (NLRs)
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21
Q

describe TLRs

A

membrane proteins

found on plasma membrane and on endosomal membranes

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22
Q

describe RLRs

A

sense virus in cytoplasm

signal through a mitochondrial located pathway

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23
Q

which is the most famous DNA sensor?

A

cGAS

signals to a molecule called STING found on ER

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24
Q

describe the steps to interferon induction

A
  • PRRs (e.g. RIG-1 like receptors) detect PAMPs
  • RIG-1 then signal through Mavs on mitochondria
  • this triggers signalling through pathways
  • results in translocation of molecules from cytoplasm to nucleus
  • TFs become phosphorylated
  • bind to promoter regions of target genes (e.g. IFN beta)
  • will generate IFN beta transcripts
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25
Q

how are viruses detected when in endosome of host cell?

A
  • nucleic acids exposed inside endosomes
  • TLRs can sense nucleic acids in endosome
  • will signal to a molecule outside endosome
  • this will then send various TFs to nucleus of cell
  • switches on expression of IFN alpha
26
Q

how is virus RNA detected?

A
  • single stranded RNA is PAMP

- if RNA doesn’t look like normal host RNA it will be detected

27
Q

what is cGAS?

A
  • main way DNA viruses are sensed
  • is an enzyme that binds to dsDNA in cytiplasm
  • synthesises cGAMP
  • this diffuses to STING on ER
  • triggers phosphorylation of same set of signalling molecules and TFs that RNA viruses were triggering
28
Q

describe IFN receptors

A
  • heterodimers of IFNAR1 and IFNAR2

- binds to receptors, signals to nucleus to switch on transcription of a whole set of interferon stimulated signals

29
Q

describe IFN type 1 signalling

A
  • heterodimeric receptor (IFNAR1 and IFNAR2)
  • capable of sensing IFN alpha/beta
  • if IFN binds to receptor, will activate Jak and Tyk
  • these go on to phosphorylate STAT molecules
  • STAT molecules dimerise and combine with IRF9
  • this foes to nucleus and binds to promoter region responsibe to taht TF
30
Q

name some interferon stimulated genes

A
  • PKR
  • PML bodies
  • ADAR
  • Apoptosis
  • cell cycle arrest
31
Q

what is IFITM3 and where does it sit?

A
  • interferon induced transmembrane protein 3

- sit on membrane of endosomes in cells that have been previously stimulated with interferon

32
Q

what does IFITM3 do?

A
  • if flu virus trieds to enter cell, normally passes through endosomal pathway
  • fuses membrane with endosomal membrane
  • release contents into cytoplasm
  • if IFITM3 expressed, virus cannot do that
  • virus gets trapped in endosome
  • IFITM3 modifies membrane, prevents virus being able to fuse with endosomal membrane
33
Q

what are Mx1 and Mx2?

A
  • antiviral mediators
  • GTPase with a homology to dynamin
  • Mx can form multimers that wrap around nucleocapsids of incoming viruses
  • Mx1 = inhibits influenza
  • Mx2 = inhibits HIV
34
Q

what does the antiviral mediator, protein kinase R do?

A
  • phosphorylates alpha subunit eIF2
  • eIF2 important in translation
  • if you permanently phosphorylate alpha subunit of eIF2, ribosomes can’t binds onto mRNA and translate any genes
  • when PKR is activated in cell, no new genes translated
35
Q

what does PKR also phosphorylate?

A

NFKB

important TF that is part of interferon and inflammatory response

36
Q

what happens if you don’t switch on these genes?

A

cells infected by virus

virus could kill cell

37
Q

how long does IFN response last?

A
  • may only be maintained for several hours
38
Q

how is the ability to respond to IFN lost?

A
  • due to -ve regulation
  • SOCS genes suppress cytokine signalling and turn off response
  • if SOCS genes are switched on, even if IFN is bound to receptor, signals won’t get through
  • no new PKR made
39
Q

how do viruses evade IFN response?

A
  • avoid detection by hiding PAMP
  • intefere globally with host cell gene expression or protein
  • inhibit IFN signalling
  • block action of individual IFN induced antiviral enzymes
  • activate SOCS
  • replication strategy that is insensitive to IFN
40
Q

What is NS3/4? How is it linked to what MAVS does?

A
  • protease that acts as antagonist to interferon induction by cleaving MAVS
  • MAVS important in detecting Hep C through RIG-1 pathway
41
Q

what happens if there is Hep C?

A
  • Hep C entering a cell will be detected by RIG-1 receptors
  • this then signals to MAVS
  • this then switches on IFN response
  • But Hep C rapidly synthesises NS3/4 which cleaves MAVS away from mitochondrion and prevents signal from getting through
42
Q

how does influenza interfere with interferon?

A
  • acts as an antagonist to interferon induction by binding to RIG-1/ TRIM25/ RNA complex
  • prevents activation of signalling pathway
  • prevents nuclear processing of newly induced genes
43
Q

what does influenza normally do?

A
  • trigger RIG-1 via production of viral RNA in cytoplasm

- this signals to MAVS

44
Q

how does NS1 protein in influenza interfere?

A
  • NS1 protein in influenza binds to RIG/ Trim25 complex which is detecting viral RNA
  • stops it from triggering this pathway
  • NS1 migrates to nucleus
  • prevents export of newly synthesised genes
45
Q

what do pox viruses consist of?

A
  • more than half of pox virus genome made of accessory genes that modify immune response
46
Q

what do pox viruses encode?

A

soluble cytokine receptors

mop up IFN and prevent it from ever reaching receptor

47
Q

how does HIV deal with restriction factors?

A
  • using accessory genes
  • Vif targets APOBEC
  • Vpu targets tetherin
48
Q

what is APOBEC3G?

A

apolipoprotein B mRNA-editing enzyme catalytic polypeptide like 3G

49
Q

what is APOBEC3G involved in?

A

innate immune resistance to retroviruses and hepadnaviruses

it modifies some of the nucleotides

50
Q

what modifications does APOBEC3G make?

A
  • deaminated dC to dU in minus strand viral cDNA during reverse transcriptase
  • = G to A hypermutation leading to error catastrophy
  • virus can’t propagate and make new versions of itself
51
Q

how does HIV target APOBEC3G?

A
  • HIV encodes small accessory protein = Vif
  • Vif counteracts activity of host innate protection factor APOBEC
  • no Vif means APOBEC can modify reverse transcript of viral genome
  • induces hypermutation so virus doesn’t propagate
  • vif targets APOBEC for degradation
  • not enough APOBEC to be incorporated into virus and interfere w/ reverse transcriptase
52
Q

where does tetherin sit?

A

on cell surface of virus infected cells

53
Q

what does tetherin do?

A
  • as virus tries to escape to go and infect other cells, tetherin grabs hold of virus
  • prevents it being released from infected cell
54
Q

what does Vpu do?

A

pulls tetherin back from cell surface

targets it for degradation and gets rid of it

55
Q

how does ebola counteract our immune mechanisms?

A

encodes 2 proteins:

  • VP35 - inhibits RIG-1 protein
  • VP24 - stops signal from getting through from IFN beta receptor to nucleus
  • so virus can continue to replicate unchecked
56
Q

what is a consequence of innate immunity?

A
  • damage infected cell by virus
  • damage of infected and bystander cells by immune response
  • host sense presence of virus and switches on sets of genes to try and stop virus
57
Q

what does transcriptomimics do?

A
  • reveal skewing of IFN response by different viruses

- way of measuring how much mRNAs get switched up

58
Q

what do proteomics do?

A
  • reveal viral control of protein expression

- method of counting the proteins that get made from various transcripts

59
Q

what is the cytokine storm?

A
  • virus replicated and induces high levels of IFN
  • accompanied by massive release of TNF alpha and other cytokines
  • lot of virus and lot of cytokines
60
Q

what does a cytokine storm lead to?

A
  • pulmonary fibrosis (accumulation of immune cells in lung spaces)
  • eventually pt will succumb to immune pathology rather than from direct damage from virus
61
Q

what is the good thing about type 3 interferons?

A
  • cannot signal through receptors present on immune cells
  • T1 can signal immune cells and induce some form of immunopathology (make pt feel sick)
  • T3: only signals epitheial cells so can induce antiviral state in these target cells (no knock on side effects of inflammation)
62
Q

how can oncolytic viruses take advantage of IFN def state?

A
  • cancer cells deficient in ability to mount proper interferon response
  • a virus that is unable to overcome an interferon response will not be able to replicate in healthy cells but can replicate in tumour cells and kill them