Interferon Flashcards
What is interferon?
Transferrable factor produced when the cells are exposed to virus- like a danger signal
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)
What is the first interferon to be produced in a viral infection?
IFN beta
Which organ is IFN lambda very important in?
Liver
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
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
Describe RIG-I signalling.
RIG-I like receptors will recognise single stranded RNA in the cytoplasm of the cell and it will signal through MAVS (mitochondrial)
This will signal further downstream, leading to generation of IFN-beta transcripts
Describe TLR signalling.
TLR detects nucleic acids in the endosome (this isn’t normal)
It will signal to molecules outside the endosome (MyD88) and send various transcription factors to the nucleus
It will result in the switching on of expression of IFN alpha
Describe DNA sensing.
Mainly done by cGAS
This is an enzyme that binds to dsDNA in the cytoplasm and synthesises cGAMP (second messenger)
cGAMP diffuses to STING (found on endoplasmic reticulum)
This triggers phosphorylation of the same sets of transcription factors and signalling molecules the RNA viruses were triggering
Describe the structure of IFN receptors for IFN alpha and IFN beta
They are heterodimers of IFNAR 1 and IFNAR 2
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
When is PKR activated by cells?
It is an extreme measure and a last resort – only activated when the cell has no other option
Name a family of genes that suppress the cytokine signalling and turn off the response.
SOCS
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
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
Explain how influenza controls the interferon response.
NS1
Acts an antagonist to interferon induction by binding to the RIG-I/TRIM25/RNA complex and preventing activation of the signalling pathway
It also prevents nuclear processing of newly induced genes
NS1 also migrates to the nucleus where it prevents the export of newly synthesised genes
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
Describe a potential therapeutic use of this feature
This could be useful in autoimmune or inflammatory conditions where IFN and other cytokines are produced in abundance
What are two proteins produced by Ebola virus that are particularly important in dealing with the immune response?
VP35
VP24
What do these proteins do?
VP35 – inhibits the RIG-I pathway
VP24 – stops the signal getting through from the IFN beta receptor to the nucleus (stops the STAT1 molecule from getting to the nucleus)
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
What is a serious consequence of cytokine storm?
Pulmonary fibrosis – due to accumulation of immune cells in the lungs
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
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
What disease is IFN used to treat?
Hepatitis C (a combination of pegylated IFN is used with ribavirin
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
Common intrinsic defense against virus
Viruses have a large ratio of C then G in their genome compared to humans. ZAP protein can recognise this in RNA and will result in degradation of this foreign RNA by an RNA exosome
3 functions of type 1 interferons- these are produced first
Induce antimirobial state in infected and neighbouring cells
Modulate innate response to promote NK cells
Activate adaptive immune response
What are the type 1 IFNs
IFN alpha and beta
What cells secrete IFN beta
All cells
What cells produce IFN alpha
Just plasmacytoid dendritic cells
Transcription factor for IFN beta production induction
IRF-3
Transcription factor for IFN alpha production induction
IRF-7
Difference in genes for IFN alpha and beta
1 for beta
14 for alpha
What receptor do type 1 IFN bind to
IFNAR which is on all cells
What is type 2 IFN
IFN gamma
Which cells produce type 2 IFN
T cells
NK cells
Receptor for type 2 interferons
IFNGR
What is type 3 IFN
Lamda
Receptors for type 3 IFN
IL28R
IL10 beta
Found on epithelial cells
How do we differentiate self from non self
PAMPs- for example DNA in cytoplasm which are detected by Pattern Recongntion Receptors
Examples of cytoplasmic PRRs
RLRs
TLRs
Way of detecting DNA in cytoplasm
cGAS
How does cGAS work
If binds to DNA in cytoplasm enzyme is switched on producing cGAMP that binds toSTING protein on ER membrane- this acts as signalling
What happens once PRRs have been activated
Production of IFN BETA that is soluble cytokine
Common inborn genetic errors leading to lack of interferon production
IRF 7- lack of IFN alpha
IFNAR
IRF
Examples of interferon stimulated genes
Proerin kinase A that inhibits translation
Serpine activates protein
ADAR induces errors in viral replication
IFITM3 restricts virus entry via endosomes
