Interferon Flashcards
What is the most common cause of sporadic encephalitis worldwide? Which subset of the population is this most common in?
Herpes simplex encephalitis
Children: affecting previously healthy individuals on primary infection with HSV-1
What is interferon?
Transferrable factor produced when cells are exposed to virus
What is the effect of interferon binding to interferon receptors on cells?
Signals the de novo transcription of 100s of interferon stimulated genes (ISG)
What are the 3 functions of type I interferons?
Induce antimicrobial state in infected + neighbouring cells
Modulate innate immune response to promote antigen presentation + NK cells
Activate the adaptive immune response
What are the type I interferons?
IFN alpha + IFN beta
What is the first interferon to be produced in a viral infection?
Which cells produce this?
IFN beta
All cells produce IFN beta + 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. What do these cells express high levels of?
Plasmacytoid dendritic cells
IRF-7
How many genes are there for IFN alpha and IFN beta?
Alpha: 13/14 isotypes
Beta: 1
Which IFN comes under type II interferon?
Which cells produce this? Which receptor do these signal through?
IFN-gamma: specialist immune signalling molecule
Produced by activated T cells+ NK cells
IFNGR
Which IFN falls under type III IFN? Which receptors do type III IFNs signal through?
IFN-lambda
L-28 receptors
IL-10 beta receptors
Where are L-28 and IL-10 beta receptors mainly present?
Epithelial surfaces
E.g. respiratory epithelium
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)
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, mainly found in Plasmacytoid dendritic cells
Describe RIG-I signalling.
RIG-I like receptors recognise ssRNA in the cytoplasm + signal through MAVS (mitochondrial)
Signals downstream, leading to phosphorylation of IRF3 which then dimerises + acts as a TF for generation of IFN-beta
Describe TLR signalling.
TLR detects nucleic acids in the endosome (not normal)
Signals to molecules outside the endosome (MyD88) + sends various TF’s to the nucleus
Results in switching on of expression of IFN alpha + beta
Describe DNA sensing.
Mainly done by cGAS
= enzyme that binds to dsDNA in the cytoplasm + synthesises cGAMP (2nd messenger)
cGAMP binds to STING (found on endoplasmic reticulum)
Triggers phosphorylation of IRF3, IRF3 dimerises, enters nucleus as TF, promotes synthesis of IFN beta
Describe the structure of IFN receptors for IFN alpha and IFN beta
Heterodimers of IFNAR 1 + IFNAR 2
Describe the signalling from IFNAR receptors
Binding leads to signalling cascade involving JAK + STAT
Results in phosphorylation of STAT molecules
STAT molecules dimerise + enter nucleus
Bind to a promoter + regulates transcription of 100s of new genes
What is IFITM3? What does lack of IFITM3 result in?
Sits on membrane of endosomes
Prevent fusion of virus membrane with endosomal membrane so virus gets trapped in the endosome
Lacking IFITM3 results in more severe influenza
What are Mx1 and Mx2?
Mx can form multimers that wrap around nucleocapsids of incoming viruses: nullifies the viral genomes
Mx1: inhibits influenza
Mx2: inhibits HIV
Describe the actions of Protein Kinase R. When is PKR activated by cells?
Prevents ribosomes from binding to mRNA so NO NEW genes will be TRANSLATED
An extreme measure + 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 6 mechanisms of viral evasion of the IFN response.
Avoid detection by hiding the PAMP Interfere globally with host cell gene expression +/or protein synthesis Block IFN induction cascades Inhibit IFN signalling Activate SOCS Replication strategy insensitive to IFN
Explain how hepatitis C controls the interferon response.
NS3/4 protease cleaves MAVS
MAVS is important in detecting Hep C through the RIG-I pathway
Thus Hep C is not detected
Explain how influenza controls the interferon response.
NS1 protein
Acts an antagonist to IFN induction by binding to the RIG-I complex + preventing activation of the signalling pathway
Also prevents nuclear processing of newly induced genes
What type of virus are Pox and Herpes viruses? What does this allow them to encode?
Large DNA viruses
Encode accessory genes to evade immune responses
What do Pox viruses encode that helps deal with the interferon response?
Encode soluble cytokine receptors that mop up IFN + prevent it from reaching its receptors
Describe a potential therapeutic use of the soluble cytokine receptors encoded by Pox viruses
Could be useful in AI or inflammatory conditions where IFN + other cytokines are produced in abundance
What can result from viruses interfering with the immune response?
Skewing of immune response resulting in immunopathology
Describe how viral infections can cause cytokine storm.
Lots of virus propagation, induces high IFN production
accompanied by massive release of TNF alpha + 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 can’t control interferon can be used as the next generation of live attenuated vaccines.
They’re able to infect cells + will replicate sufficiently to be able to mount an immune response but won’t replicate to the extent where it causes disease
Viruses that can’t control interferon can’t be propagated in normal healthy cells. What is the solution to this issue?
Propagate in cells deficient in IFN response
Explain why interferons are not frequently used as an antiviral therapy.
Stimulate production of several cytokines which cause unpleasant side effects
What disease has IFN been used to treat?
Hepatitis C
Explain the reasoning behind using IFN-lambda as a treatment for influenza.
Receptors for IFN lambda are only found on epithelial surfaces (site of infection of influenza)
IFN lambda can’t signal through immune cells + cause immunopathology
Only induces an antiviral state in epithelial cells
Explain how oncolytic viruses would work.
Viruses engineered to uniquely replicate in tumour cells + kill them
Cancer cells are unable to mount a proper IFN response
So, a virus unable to control the IFN response will NOT be able to replicate in healthy cells but will be able to infect + replicate in cancer cells
What can lead to increased susceptibility to herpes simplex virus, thus resulting in encephalitis?
Inborn errors of certain genes result in lack of CNS intrinsic interferon response
Give 2 examples of viruses that can trigger a cytokine storm
Dengue haemorrhage fever
Sever influenza
