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 production induced by?
IRF-3
Name a cell type that is specialised for producing IFN alpha.
Plasmacytoid dendritic cells
What do these plasmacytoid dendritic cells express high levels of?
IRF-7
How many genes are there for IFN alpha and IFN beta?
Alpha – 13/14 isotypes of genes
Beta – ONE
Which IFN comes under type II interferon?
IFN-gamma - specialist immune signalling molecule
Which cell types produce IFN-gamma?
Produced by activated T cells and NK cells
Which receptor do these IFN2’s signal through?
IFNGR
Which IFN falls under type III IFN?
IFN-lambda
Which receptors do type III IFNs signal through?
IL-28 receptors
IL-10 beta receptors
Where are these type III IFN 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 often sense nucleic acids (include RLR, TLR, NLR)
- PAMPs (pathogen-associated molecular patterns)
Name three 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
- NOD like receptors (NLR’s)- cytoplasmic
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 antiviral-signaling protein)
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 that the cytoplasmic PAMP dsRNA causes
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
On the membrane of endosomes, in cells that have been previously stimulated by IFN.
Restricts virus entry through endoscopes so the virus is broken down by acidic pH
NOTE: mice and people lacking IFITM3 get more severe influenza
What are Mx1 and Mx2 and what are their functions?
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 (Suppressor of cytokine signalling)
note: IFN response only maintained for a few hours
subsequently ability to respond to IFN is lost due to negative regulation by SOCS genes to turn off IFN response
so antiviral state does not last
State some mechanisms of viral evasion of the IFN response.
HIBIBAR
- Virus hides the PAMPS e.g inside vesicle
- Interfere with host cell gene expression and/or protein synthesis
- Block IFN induction cascades
- Inhibit IFN signalling
- Block action of individual IFN-induced antiviral enzymes
- Activate SOCS
- Replication that is insensitive to IFN
Explain the mechanism of viral evasion in Hepatitis C
how it controls interferon response
NS3/4 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 the mechanism of viral evasion in Influenza
how it controls 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 interferon response?
- They encode soluble cytokine receptors (vaccinia virus B18) that mop up IFN and prevent it from reaching its receptors
- Also half their genome is comprised of accessory genes that can modify immune responses
Describe a potential therapeutic use of this feature of Pox viruses
This could be useful in autoimmune or inflammatory conditions where IFN and other cytokines are produced in abundance
What are three proteins produced by Ebola virus that are particularly important in dealing with the immune response?
VP35
VP24
VP30
What do these proteins produced by the Ebola virus 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)
VP30- blocks RNAi expression
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
note: 100x more IFN is required for IL-6 induction (causes fever) than for Mx induction, thus more IFN stimulates a more serious response (up to cytokine storm)
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 be used 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 these 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
When would you see IFN gamma being expressed?
- Liver infections
2. Respiratory tract infections
What are polymorphisms in IFN gamma associated with?
Improved outcomes from HCV and HBV with both spontaneous clearance and response to antiviral therapy
What is the function of RLR’s?
Bind to MAVS (mitochondrial antiviral signalling protein) found on mitochondria and stimulate IFN-B production
What is the function of TLR’s?
Make IFN-A
Why is it the healthier you get (less ill) the more severe the clinical outcome?
Better at producing IFN
typical in Dengue haemorhaggic fever, Ebola and severe influenza
