Interferon Flashcards
what are the different types of interferon
type 1- IFN-alpha
type 2 IFN-gamma
type 3 IFN-lambda
what are the functions of type 1 interferons
induce antimicrobial state (local and adjacent)
modulate innate immune response- promote Ag presentation (and NK) but inhibit pro-inflammation
activate adaptive immune response
what are the different type 1 interferons
IFN-alpha- 13-14 isotopes of genes for this
IFN-beta - secreted first by ALL cells (production induced by IRF-3)- ONE gene for this
-target= IFNAR
which cells secrete IFN-alpha
plasmacytoid dendritic cells (pDC)
what are the type 2 interferons (IFN-gamma) produced by
activated T-cells and NK cells
-signals through IFNGR
what is the IFN-lambda aka type 3 receptor and where is it found
IL28R-epithelial surfaces
what are IFN-lambda polymorphisms associated with
IMPROVED outcome in HCV and HBV
what does interferon trigger the de novo production of
interferon stimulated genes (ISG’s)
give some examples of ISG’s
- PKR – cessation of gene translation
- Mx1 – inhibits influenza
- Mx2 – inhibits HIV
- apoptosis genes
- APOBEC – causes hypermutation
- tetherin – prevents release of virus to other cells
- IFITM3 – stops entry through endosomes (eg. Flu, dengue)
how is interferon induced
PRRs detect PAMPs (eg ssRNA) and signal through MAVS on mitochondrion
this results in:
-phosphorylation of transcription factors -produce IFN (TLRs produce IFN-alpha, RLRs produce IFN-beta)
-induction of antiviral state
what is the main sensor of DNA viruses
cGAS which then diffuses to STING protein on ER- induces IFN type 1
what is the main signalling pathway with type 1 IFNs
receptor is a heterodimer of INF AR1 and AR2
these dimerise when INF type 1 binds- causes JAK1 and TYK2 cross phosphorylate
this activates STAT proteins, which in turn activates:
- antiviral response (ISRE)-get fever and feel sick
- inflammatory response (GAS)
- repressors of inflammatory pathways (GAS)
ISG’s include IFITM3 and Mx1/Mx2 (these are the most important)
what is IFITM3
interferon induced transmembrane protein 3- it restricts virus entering through endosomes by preventing them from escaping, so virus is broken down by acidic pH
what are Mx1 and 2
GTPases with a homology to dynamin
-form multimers to wrap around nucleocapsids of viruses
Mx1-inhibits influenza
Mx2-inhibits HIV
why can IFN response not last that long and what regulates it
it can only last a few hours as it is toxic to the cells-
after the few hours it is turned off by SOCS (suppressor of cytokine signalling)
how do viruses evade IFN response
Hide PAMPs
Interference with host cell gene expression/protein synth
Block IFN induction cascades
Inhibit IFN signalling directly
Block activation of individual IFN induced antiviral enzyme
Activate SOCS
Replication that is insensitive to IFN
give examples of viral evasion of IFN
Hep c- NS3/4 proteases, cleaves MAVS- Interferes with IFN induction cascade
Influenza- NS1 protein- binds RIG-1/TRIM25/RNA complex- prevents activation of signalling pathway/prevents nuclear processing of newly induced genes
POX viruses/and herpes: large part of genome are accessory genes that modify immune response- encode soluble cytokine receptors that prevent INF from reaching its receptors
ebola: VP35 blocks RIG-1 like complexes
VP24 directly blocks IFN signalling
what are the potential future uses of IFN
live attenuated vaccines: viruses deficient in control of IFN
antiviral treatment: IFN can be used against viruses but has bad side effects
IFN-lambda- influenza therapeutic drug as it only stimulates antiviral state
cancer treatment- cancer cells may be deficient in IFN, so if cancer patient is given novel virus, it may be able to kill cells deficient in IFN only
