Interferon Flashcards
what is the most common cause of sporadic encephalitis in the western world?
- herpes simplex encephalitis
- most common in childhood
what are the 6 genes that are implicated with inborn errors in HSE?
- TLR3
- UNC(3B1
- TRIF
- TRAF3
- TBK1
- IRF3
what do these gene errors do?
- impairs CNS intrinsic interferon alpha/beta response to HS infection
- virus replicated to a much higher extend than would be otherwise
what is interferon?
transferable factor produced when cells are exposed to virus
what does interferon do?
- binds to specific receptors
- signals activation of de novo transcription of hundreds of interferon stimulated genes
- puts cell into an anti-viral state
what are type 1 interferons?
polypeptides secreted from infected cells
what are the 3 main functions of type 1 interferons?
- induce antimicrobial state in infected and neighbouring cells
- modulate innate response
- promotes antigen presentation and NK cells
- inhibits proinflammation
- activate adaptive immune response
what is the first interferon to be made?
- IFN beta
describe how type 1 interferons cause adaptive immune response
- 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
what are specialized cells that are good at making interferon?
- plasmacytoid dendritic cells
- particularly IFN-alpha
what are the type 1 interferons? what are they secreted from?
- IFN alpha/beta
- IFN beta secreted by ALL cells
- IFN beta induction triggered by IRF-3
where is the IFNAR receptor?
present on all tissues
how many genes are there for IFN alpha/beta?
- one gene for IFN-beta
- 13/14 isotypes of IFN-alpha
what is type 2 interferon? What produces it?
- much more specialist immune signalling molecule
- produced by immune cells (activated cells, NK cells)
- signals through IFNGR
what is type 3 interferon? where is it present?
- IFN lambda
- mainly on epithelial cells
what does type 3 interferon signal through?
- IL28 receptor
- IL10 beta
what does IFN lambda do?
- protects barriers of your body e.g. resp epithelium, gut
- important in liver
what are polymorphisms in IFN lambda gene associated with?
different outcomes from liver viruses
how do you differentiate self from non self?
- PAMPs
- PRRs
- often sense foreign nucleic acids
what are the receptors for sensing the presence of viruses?
- RLRs (cytoplasmic RIG-1 like receptors)
- TLRs (endosomal toll like receptors)
- cytoplasmic nucleotide oligomerisation domain receptors (NLRs)
describe TLRs
membrane proteins
found on plasma membrane and on endosomal membranes
describe RLRs
sense virus in cytoplasm
signal through a mitochondrial located pathway
which is the most famous DNA sensor?
cGAS
signals to a molecule called STING found on ER
describe the steps to interferon induction
- 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
how are viruses detected when in endosome of host cell?
- 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
how is virus RNA detected?
- single stranded RNA is PAMP
- if RNA doesn’t look like normal host RNA it will be detected
what is cGAS?
- 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
describe IFN receptors
- heterodimers of IFNAR1 and IFNAR2
- binds to receptors, signals to nucleus to switch on transcription of a whole set of interferon stimulated signals
describe IFN type 1 signalling
- 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
name some interferon stimulated genes
- PKR
- PML bodies
- ADAR
- Apoptosis
- cell cycle arrest
what is IFITM3 and where does it sit?
- interferon induced transmembrane protein 3
- sit on membrane of endosomes in cells that have been previously stimulated with interferon
what does IFITM3 do?
- 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
what are Mx1 and Mx2?
- 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
what does the antiviral mediator, protein kinase R do?
- 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
what does PKR also phosphorylate?
NFKB
important TF that is part of interferon and inflammatory response
what happens if you don’t switch on these genes?
cells infected by virus
virus could kill cell
how long does IFN response last?
- may only be maintained for several hours
how is the ability to respond to IFN lost?
- 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
how do viruses evade IFN response?
- 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
What is NS3/4? How is it linked to what MAVS does?
- protease that acts as antagonist to interferon induction by cleaving MAVS
- MAVS important in detecting Hep C through RIG-1 pathway
what happens if there is Hep C?
- 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
how does influenza interfere with interferon?
- 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
what does influenza normally do?
- trigger RIG-1 via production of viral RNA in cytoplasm
- this signals to MAVS
how does NS1 protein in influenza interfere?
- 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
what do pox viruses consist of?
- more than half of pox virus genome made of accessory genes that modify immune response
what do pox viruses encode?
soluble cytokine receptors
mop up IFN and prevent it from ever reaching receptor
how does HIV deal with restriction factors?
- using accessory genes
- Vif targets APOBEC
- Vpu targets tetherin
what is APOBEC3G?
apolipoprotein B mRNA-editing enzyme catalytic polypeptide like 3G
what is APOBEC3G involved in?
innate immune resistance to retroviruses and hepadnaviruses
it modifies some of the nucleotides
what modifications does APOBEC3G make?
- 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
how does HIV target APOBEC3G?
- 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
where does tetherin sit?
on cell surface of virus infected cells
what does tetherin do?
- as virus tries to escape to go and infect other cells, tetherin grabs hold of virus
- prevents it being released from infected cell
what does Vpu do?
pulls tetherin back from cell surface
targets it for degradation and gets rid of it
how does ebola counteract our immune mechanisms?
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
what is a consequence of innate immunity?
- 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
what does transcriptomimics do?
- reveal skewing of IFN response by different viruses
- way of measuring how much mRNAs get switched up
what do proteomics do?
- reveal viral control of protein expression
- method of counting the proteins that get made from various transcripts
what is the cytokine storm?
- 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
what does a cytokine storm lead to?
- pulmonary fibrosis (accumulation of immune cells in lung spaces)
- eventually pt will succumb to immune pathology rather than from direct damage from virus
what is the good thing about type 3 interferons?
- 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)
how can oncolytic viruses take advantage of IFN def state?
- 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
