Interferon Flashcards
Type I interferons
Interferon alpha and interferon beta
- Interferon beta secreted by all cells and IFNAR receptor is present on all tissues
- Interferon beta induction triggered by IRF-3
- plasmacytoid dendritic cells (PDCs) are specialist interferon alpha secreting cells=express high levels of IRF-7 constitutively
- one gene for interferon beta and 13/14 isotypes of interferon alpha
Type II interferons
Interferon gamma
- produced by activated T cells and natural killer cells
- signals through a different receptor IFNGR
Self and non-self differentiation
- PAMPS=pathogen associated molecular patterns
- PRRs=pattern recognition receptors
- often sense foreign nucleic acid
- RLRs=cytoplasmic RIG-I like receptors
- TLRs=endosomal toll like receptors
- NLRs=cytoplasmic nucleotide oligomerisation domain receptors
Herpes simplex encephalitis
- most common cause of sporadic encephalitis in western world
- 1/10,000 prevalence
- most common in childhood, affecting previously healthy individuals on primary infection with HSV-1
Interferon stimulated genes
- PKR=protein kinase R=inhibits translation
- 2’5’OAS=activates RNAse L that destroys single stranded RNA
- Mx=inhibits incoming viral genomes
- ADAR=induces errors during viral replication
- Serpine=activates proteases
- Viperin=inhibits viral budding
Antiviral mediators
Mx1 and Mx2
- GTPase with homology to dynamin
- Mx can form multimers which wrap around nucleocapsids of incoming viruses
- Mx1 inhibits influenza
- Mx2 inhibits HIV
Antiviral state
- self regulates to limit damage
- interferon response may only be maintained for several hours=ability to respond to interferon is lost due to negative regulation
- SOCS suppressor of cytokine signalling genes turn off response
Viral strategies to evade interferon response
- Avoid detection by hiding PAMP
- Interfere globally with host cell gene expression and/or protein synthesis
- Block interferon induction cascades by destroying or binding
- Inhibit interferon signalling
- Block action of individual interferon induced antiviral enzymes
- Activate SOCS
- Replication strategy that is insensitive to interferon
Hep 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 signalling pathway activation=also prevents nuclear processing of newly induced genes
Pox viruses
- prevent signal getting through
- Pox and herpes viruses are large DNA viruses
- more than half of pox virus genome is comprised of accessory genes that modify immune response
- Pox viruses encode soluble cytokine receptors (vaccinia virus B18)=being developed as possible future immune therapies
Consequences of innate immunity
-combination of damage of infected cells by virus and damage of infected and bystanders cells by immune response
Interferon interference leads to viruses skewing the immune response
- many viruses modulate immune response=presumably to increase own replication and transmission=can result in inadvertant pathology
- effects of interferon can vary from protective to immunopathologic=may depend on how much interferon is made
Cytokine storm
INNATE IMMUNOPATHOLOGY OF VIRUS INFECTIONS
- virus replicates, induces high interferon accompanied by massive TNFalpha and other cytokines
- differences in clinical outcome may reflect vigour of innate immune system=may vary with age
- typically of Dengue haemorrhagic fever, severe influenza infections and Ebola
Consequences of balance between viruses and interferons
- host range barriers
- therapeutics
- vaccines
- oncolytic viruses
Interferons as an antiviral treatment
- interferon as a treatment (HCV, pegylated IFN often used with ribavirin)
- associated with unpleasant side effects
Use of live attenuated vaccines
- viruses deficient in interferon control are attenuated in interferon competent cells
- high interferon levels they induce can also recruit useful immune cells, interferon acting as an adjuvant
- cells naturally or engineered to be deficient in interferon response can be used to grow attenuated virus strains
Interferon
- transferable factor produced by exposure of eggs to heat inactivated influenza virus that protected new cells from infection
- binds to specific receptors and signals activation of de novo transcription of hundreds of interferon stimulated genes
Type I interferon functions
POLYPEPTIDES SECRETED FROM INFECTED CELLS
Three major functions:
1) induce antimicrobial state in infected and neighbouring cells
2) modulate innate response to promote antigen presentation and natural killer cells
3) activate adaptive immune response
Type III interferons
Interferon lambda
-signals through receptors IL28R and IL10beta=mainly present on epithelial surfaces
