Interferon Flashcards
What is herpes simplex encephalitis?
Most common cause of sporadic encephalitis in the western world.
Prevalence of 1/10,000.
Most common in childhood, affecting previously healthy individuals on primary infection with HSV-1.
Inborn errors in at least 6 genes implicated in HSE: TLR3, UNC93B1, TRIF, TRAF3, TBK1, and IRF3.
Impair CNS intrinsic interferon alpha/beta response to HSV infection.
What is interferon?
A transferable factor discovered more than 50 years ago that was produced by exposure of eggs to heat inactivated influenza virus and protected new cells from infection.
Binds to specific receptors and signals activation of de novo transcription of hundreds of interferon stimulated genes, ISGs.
What are type I interferons?
Polypeptides secreted from infected cells.
What are the three major functions of type I interferons?
Induce antimicrobial state in infected and neighbouring cells.
Modulate innate response to promote Ag presentation and NK but inhibit pro-inflammation.
Activate the adaptive immune response.
What types of cells make type I interferons?
Epithelial cells
Fibroblasts
Macrophages
Plasmacytoid dendritic cells
Dendritic cells
What are type I interferons?
IFN-alpha and IFN-beta.
IFN-beta is secreted by all cells and IFNAR receptor is present on all tissues.
IFN-beta induction is triggered by IRF-3.
Plasmacytoid dendritic cells are specialist IFN-alpha secreting cells that express high levels of IRF-7 constitutively.
One gene for IFN-beta, 13/14 isotypes of IFN-alpha.
What is type II interferon?
IFN-gamma.
Produced by activated T cells and NK cells.
Signals through a different receptor IFNGR.
What is type III inteferon?
IFN-lambda.
Signals through receptors IL28R and IL10-beta that are mainly present on epithelial surfaces.
Important at epithelial surfaces.
Polymorphisms in IFN-lambda associated with improved outcome from HCV and HBV both spontaneous clearance and response to antiviral therapy.
How is self differentiated from non-self material?
Pathogen associated molecular patterns, PAMPs- unique to each virus
Pattern recognition receptors, PRRs- recognise viral PAMPs
Often sense foreign nucleic acid
Cytoplasmic RIG-I like receptors RLRs
Endosomal Toll like receptors, TLRs
Cytoplasmic nucleotide oligomerisation domain receptors NLRs
How is viral DNA detected by host cells?
cGAS pathway
DNA in cytoplasm- sensors in cytoplasm detect DNA, bind it and synthesise cGAMP
Signals through STING, IRF3 moves into nucleus and transcribes new interferon messages.
What does the cell do when it detects viral DNA/RNA?
Makes interferon beta, which is made into protein and secreted from the infected cell.
Acts on interferon receptors on every cell to activate pathway that makes interferon stimulated genes.
Antiviral signals.
Autocrine and paracrine.
List examples of interferon stimulated genes.
PKR protein kinase R: inhibits translation
2’5’OAS: activates RNAse L that destroys ssRNA
Mx: inhibits incoming viral genomes
ADAR: induces errors during viral replication
Serpine: activates proteases
Viperin: inhibits viral budding
What is IFITM3?
Interferon induced transmembrane protein 3.
Interferon stimulated gene.
Restricts virus entry through endosomes.
When overexpressed, membranes of endosomes become rigid and virus cannot escape into cell.
e.g. influenza virus
What are antiviral mediators?
Mx1 and Mx2.
GTPase with homology to dynamin.
Mx can form multimers which wrap around the nucleocapsids of incoming viruses.
Mx1 inhibits influenza.
Mx2 inhibits HIV.
How long does the antiviral state of IFN response usually last?
Maintained for several hours.
Subsequently the ability to responde to IFN is lost due to negative regulation.
SOCS (suppressor of cytokine signalling) genes turn off the response.
How do viruses evade the IFN response?
Avoid detection by hiding the PAMP.
Interfere globally with host cell gene expression and/or protein synthesis.
Block IFN induction cascades by destroying or binding.
Inhibit IFN signalling.
Block the action of individual IFN induced antiviral enzymes.
Activate SOCS.
Replication strategy that is insensitive to IFN.
Give examples of interferon control by viruses (stopping activation).
Hepatitis C virus: NS3/4 protease acts as antagonist to interferon induction by cleaving MAVS.
Influenza virus: NS1 protein acts as antagonist to interferon induction by binding to RIG-I/TRIM25/RNA complex and preventing activation of signalling pathway, and also prevents nuclear processing of newly induced genes.
What is the consequence of viruses skewing the immune response?
Many viruses modulate the immune response, presumably to increase their own replication and transmission.
This can result in inadvertent pathology.
The effects of interferon can vary from protective to immunopathologic.
This may depend on how much interferon is made- 100 times more IFN is required for IL-6 induction than for Mx.
What is the cytokine storm?
Innate immunopathology of virus infections.
Virus replicates, induces high IFN accompanied by massive TNF-alpha and other cytokines.
Differences in clinical outcome may reflect vigour of innate immune system, which may vary with age.
This is typical of Dengue haemorrhagic fever, severe influenza infections and Ebola.
What are the mediators of a cytokine storm?
TNF
IFN-alpha/beta
IFN-gamma
IL-1-alpha/beta
IL-6
CCL2
Is IFN used as an antiviral treatment?
Used to be used for hepatitis C virus, pegylated IFN often used with ribavirin.
Associated with unpleasant side effects, so not anymore.
How may IFN-lambda be used as an influenza therapeutic?
Only expressed on epithelial cells.
Not able to signal to immune cells- no IFN-lambda receptors on immune cells.
Switch on antiviral state in epithelial cells, no immunopathology from effects on immune cells.
How may viruses be used as live attenuated vaccines?
Viruses deficient in control of IFN are attenuated in IFN competent cells.
The high IFN levels they induce can also recruit useful immune cells, IFN acting as an ‘adjuvant’.
Cells naturally or engineered to be deficient in IFN response can be used to grow these attenuated virus strains.
