Interferon Flashcards
What is the most common cause of sporadic encephalitis worldwide?
Herpes simplex encephalitis
Which subset of the population is herpes encephalitis most common in?
Most common in childhood – affecting previously healthy individuals on primary infection with HSV-1
What is interferon?
Transferrable factor produced when the cells are exposed to virus
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 are the three functions of type I interferons?
Induce antimicrobial state in infected and neighbouring cells
Modulate innate immune response to promote antigen presentation and NK cells but inhibit proinflammation
Activate the adaptive immune response
What are the type I interferons?
IFN alpha and IFN beta
What is the first interferon to be produced in a viral infection?
IFN beta
Which cells produce IFN beta?
All cells produce IFN beta and all tissues have IFNAR receptors
What is IFN beta induction triggered by?
IRF-3
Name a cell type that is specialised for producing IFN alpha.
Plasmacytoid dendritic cells
What do these cells express high levels of?
IRF-7
How many genes are there for IFN alpha and IFN beta?
Alpha – 13/14 isotypes
Beta – ONE
Which IFN comes under type II interferon?
IFN-gamma - specialist immune signalling molecule
Which cell types produce this IFN?
Produced by activated T cells and NK cells
Which receptor do these IFNs signal through?
IFNGR
Which IFN falls under type III IFN?
IFN-lambda
Which receptors do type III IFNs signal through?
L-28 receptors
IL-10 beta receptors
Where are these receptors mainly present?
Epithelial surfaces
E.g. respiratory epithelium and gut
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
Describe the signalling from IFNAR receptors
IFN binds and the IFN receptor activates Jak and Tyk, which goes on to phosphorylate the STAT molecules
STAT molecules dimerise and combine with IRF-9
It then goes to the nucleus, binds to a promoter and regulates transcription
What is IFITM3?
Interferon-induced transmembrane protein 3
These sit on the membrane of endosomes, in cells that have been previously stimulated by IFN
It prevents fusion of the virus membrane with the endosomal membrane so the virus gets trapped in the endosome
NOTE: mice and people lacking IFITM3 get more severe influenza
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
Describe the actions of Protein Kinase R.
It phosphorylates the alpha subunit of eIF2 (initiation factor) that is important in translation
This prevents ribosomes from binding to mRNA so NO NEW GENES WILL BE TRANSLATED
It also phosphorylates NFkB, which is an important transcription factor that is part of the interferon and inflammatory response
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 type of virus are Pox and Herpes viruses?
Large DNA viruses
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
Name two proteins produced by HIV that helps deal with restriction factors and state what they target.
Vif – APOBEC
Vpu – Tetherin
Describe the normal action of APOBEC.
APOBEC is involved in the innate immune resistance to retroviruses and hepadnaviruses
APOBEC modifies some of the nucleotides in reverse transcription and makes them into the wrong version
APOBEC deaminates dC to dU in the minus strand of viral cDNA during reverse transcription
This leads to G to A hypermutation resulting in ERROR CATASTROPHE
This results in so many mutations that the viral genome becomes nonsense and the virus can’t replicate
What is the effect of Vif on APOBEC?
Vif counteracts the activity of APOBEC and targets it for degradation
This removes the interference of APOBEC with reverse transcription
Describe the normal action of tetherin.
Tetherin sits on the cell surface of infected cells and binds to viruses that try to escape the cell to go and infect other cells
This limits the spread of viral infection
What is the effect of Vpu on tetherin?
Vpu pulls tetherin back from the cell surface and targets it for degradation
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)
What two techniques can be used to observe the skewing of the immune response by viruses?
Transcriptomimics – shows changes in mRNA production
Proteomimics – shows changes in protein expression
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
The downside of this feature of the viruses is that these virus particles can’t be propagated in normal healthy cells. What is the solution to this issue?
Propagate the viruses in cells that are deficient in the IFN response
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
Explain how oncolytic viruses would work.
Viruses are engineered that can uniquely replicate in tumour cells and kill them
Generally speaking, cancer cells are deficient in their ability to mount a proper interferon response
So, a virus that is unable to control the IFN response will NOT be able to replicate in normal healthy cells but they will be able to infect and replicate in cancer cells
