Flashcards in Interferon Deck (48)
What is the most common cause of sporadic encephalitis worldwide?
Herpes simplex virus causing 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
Promote antigen presentation by APC cells
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?
Which cells produce IFN beta?
All cells produce IFN beta and all tissues have IFNAR receptors
Which transcription factor triggers IFN beta induction?
Name a cell type that is specialised for producing IFN alpha.
Plasmacytoid dendritic cells
What do these cells express high levels of?
How many genes are there for IFN alpha and IFN beta?
Alpha – 13/14 isotypes
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 IFNs signal through?
Which IFN falls under type III IFN?
Which receptors do type III IFNs signal through?
IL-10 beta receptors
Where are these receptors mainly present?
E.g. respiratory epithelium and gut
Which organ is IFN lambda very important in?
How does the innate immune system recognise non-self?
PRRs (pattern recognition receptors) on innate immune cells recognise
PAMPs (pathogen-associated molecular patterns)
NOTE: PAMPS are often viral nucleic acids and PRR often detects these
Name two types of PRRs 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
Describe RIG-I signalling.
How RLRs work
ssRNA is foreign (a PAMP), likely from a virus
RigI binds to it and then signals Mavs (mitochondria antiviral signaling protein) which is on the mitochondrial membrane
Mavs signals various different downstream pathways that eventually lead to IRF3 and IRF7 phosphorylation within the cytoplasm (this is all you need to know)
IRF3 and IRF7 dimerise and enter nucleus to act as transcription factors by binding to promoter regions
Eg This leads to transcription of IFN beta gene which would lead to IFN Beta protein that travels to neighbouring cells and induces an antiviral state (by binding onto IFNAR receptors)
Describe TLR signalling.
A lot of viruses enter via endosomes.
There are TLR receptors on the membrane of endosomes
Viral DNA (PAMP) is detected by TLRs
This triggers activation of IRF3 and IRF7 which act as transcription factors that enter the nucleus
This leads to transcription of Type 1 interferons like IFNalpha or beta.
These can leave the cell, bind to receptors on other neighbouring cells etc.
Describe DNA sensing.
cGAS senses viral DNA in cytoplasm
cGAS synthesizes a dinucleotide called cGAMP
cGAMP is detected by a protein that sits on the membrane of rough ER called STING
STING gets phosphorylated which then causes the same thing as the defence against RNA viruses:
IRF3 is phosphorylated and activated
IRF3 is the transcription factor for production of interferons
Describe the structure of IFN receptors for IFN alpha and IFN beta
They are heterodimers of IFNAR 1 and IFNAR 2
Describe the signalling pathway induced by binding of interferons to IFNAR receptors
IFN from adjacent cells bind to an interferon receptor (IFNAR)
This triggers the jak-stat pathway
This signaling pathway eventually leads to transcription of various anti-viral, interferon stimulated genes in adjacent cells
What is IFITM3?
Interferon-induced transmembrane protein 3
This is another ISG and Production of this protein is triggered by interferons and this protein sits in the endosomal membrane and stops virus from escaping endosomes. This protein is important in the defence against influenza
What are Mx1 and Mx2?
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
Main point: inhibits translation. This is good against virus BUT it also means your host cell cant translate physiological proteins. This response is almost suicidal but it will stop the virus from spreading to nearby cells
It also phosphorylates NFkB, which is an important transcription factor that is part of the interferon and inflammatory response