interferons Flashcards
What is an interferon
Interferon (IFN) is a soluble cytokine secreted by infected cells, and a ‘master regulator’ of the immune response
What are type I interferons
Polypeptides secreted from infected cells
IFN-alpha nd IFN-beta
What are the functions of type I interferons
- Induce antimicrobial state in infected and neighbouring cells
- modulate innate response to promote Ag presentation and NK
- Activate the adaptive immune response
What cells secretes IFN-beta and what is induction triggered by
IFN b is secreted by all cells and IFNAR receptor is present on all tissues.
IFNb induction is triggered by IRF-3.
What cells secretes IFN-alpha and what structure do they express
Plasmacytoid dendritic cells are specialised (though can be secreted by all cells)
They express high levels of IRF-7 constitutively
Describe the genetics of type I interferons
One gene for IFN b
13/14 isotypes of IFNa
(IFN-b made first)
What are type II interferons, what are the produced by and how does it signal
IFN-gamma
Produced by activated T cells and NK cells
Signals through its receptor IFNGR.
What are type III interferons and how does it signal
IFN-lambda
Signals through receptors IL28R (+IL10b) that are mainly present on epithelial surfaces.
What is the role of IFN-lambda
important at epithelial surface
Polymorphisms are associated with improved outcome from HCV and HBV
Which pathogenic features are involved in differentiating self form non-self
Pathogen Associated Molecular Patterns, PAMPs
Which receptors are involved differentiating self form non-selfin
Pattern Recognition Receptors, PRRs
Often sense foreign nucleic acid
Cytoplasmic RIG-I like receptors RLRs, endosomal Toll like receptors TLRs
Cytoplasmic nucleotide oligomerization domain receptors NLRs
Explain how pathogenic nucleic acid can be sensed by different receptors
Sense of viral nucleic acid via TLRs, RLRs and DNA sensors
- Interferon induction as RNA is sensed by RIG-I and/or mda-5
- TLRs sense viral RNA, especially in dendritic cells, and signal through Myd88
- DNA is sensed by cGAS that signals through STING
Describe herpes simplex encephalitis (what it is the most common cause of, prevalence and who it infects)
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.
Explain the process of IFN induction
- PAMP recognition at the cell surface signals IFNβ transcription
- IFN then has auto- and paracrine effects via IFN-𝛼 receptor on all cells
- signalling de novo transcription of interferon-stimulated genes (ISGs)
Give examples of interferon stimulated genes
Protein kinase R (PKR) - inhibits translation + activated NFkappaB
2’5’OAS - prevents translation
Mx - inhibits incoming viral genomes (movement)
ADAR - induces errors during viral replication
Serpine - activates proteases
Viperin - inhibits viral budding
How does IFITM3 restrict virus entry
Through endosomes
Stops fusion of the endosome membrane
What does Mx1 and Mx2 inhibit
Mx1 inhibits influenza, Mx2 inhibits HIV
Explain how Mx genes work
GTPase with homology to dynamin
Mx can form multimers which wrap around the nucleocapsids of incoming viruses.
Explain how antiviral state self regulates to limit damage
IFN response may only be maintained for several hours
Subsequently the ability to response to IFN is lost due to negative regulation
SOCS suppressor of cytokine signalling genes turn off the response
Give examples of how 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 viruses that can control interferon by stopping activation
Hep C
Influenza
Explain how Hepatitis C controls interferon
NS3/4 protease acts as antagonist to interferon induction by cleaving MAVS.
Explain how influenza controls interferon
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.
Explain how the sensor system is destroyed (?????????)
HCV protease NS3/4A cleaves MAVS
How do pox viruses control interferon action
Pox viruses prevent the signal getting through
More than half the pox virus genome is comprised of accessory gees that modify immune response.
Describe the overall damage caused by a virus
A combination of damage of infected cells by virus and damage of infected and bystander cells by the immune response
What occurs in the cytokine storm and give examples of diseases that may cause it
Virus replicates, induces high IFN accompanied by massive TNFa and other cytokines.
The virus is resistant to the inhibitory effects of cytokines so replicates unchecked. Thus, it induces even more IFN and even more cytokines, resulting in immune pathology and potentially death.
typical of Dengue haemorrhagic fever, severe influenza infections and Ebola.
Describe the use of IFN as an antiviral treatment
HCV, pegylated IFN often used with ribavirin
Associated with unpleasant side effects
How can viruses that lack ability to control interferon 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.
How do virus infection lead to inadvertent pathology
many viruses change the immune response to increase their own replication / transmission, and this can result in inadvertent pathology
