What is the most common cause of sporadic encephalitis worldwide?
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), these genes are what make you feel ill and carry out processes in the body to get rid of the virus.
What are the three functions of type I interferons?
Induce antimicrobial state in infected and neighbouring cells Modulate innate immune response to promote antigen presentation and NK 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
What is IFN beta induction triggered by?
Name a cell type that is specialised for producing IFN alpha.
Plasmacytoid dendritic cells
What do cells specialised for producing IFN alpha.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 does IFN-gamma signal through?
Which IFN falls under type III IFN?
Which receptors do type III IFNs signal through?
L-28 receptors IL-10 beta receptors
Where are type III IFN receptors mainly present?
Epithelial surfaces 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: they 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
Describe RIG-I signalling.
RIG-I like receptors will recognise single stranded RNA in the cytoplasm of the cell and it will signal through MAVS (mitochondrial) This will signal further downstream, leading to generation of IFN-beta transcripts. (this happens via phsphorylation of IRF-3(transcription factor) for IFN-beta transcription for all cells and in the case of plasmacytoid dendritic cels, IRF-7(transcirption factor) for IFN-alpha transcription
Describe TLR signalling.
TLR detects nucleic acids in the endosome (this isn’t normal) It will signal to molecules outside the endosome (MyD88) and send various transcription factors to the nucleus .((this happens via phsphorylation of IRF-3(transcription factor) for IFN-beta transcription for all cells and in the case of plasmacytoid dendritic cels, IRF-7(transcirption factor) for IFN-alpha transcription)
Describe DNA sensing.
Mainly done by cGAS This is an enzyme that binds to dsDNA in the cytoplasm and synthesises cGAMP (second messenger) cGAMP diffuses to STING (found on endoplasmic reticulum)(this happens via phsphorylation of IRF-3(transcription factor) for IFN-beta transcription for all cells and in the case of plasmacytoid dendritic cels, IRF-7(transcirption factor) for IFN-alpha transcription
Describe the structure of IFN receptors for IFN alpha and IFN beta
They are heterodimers of IFNAR 1 and IFNAR 2
Describe the signalling from IFNAR receptors
IFN binds and the IFN receptor activates Jak and Tyk, which goes on to phosphorylate the STAT molecules STAT molecules dimerise and combine with IRF-9 It then goes to the nucleus, binds to a promoter and regulates transcription
What is IFITM3?
Interferon-induced transmembrane protein 3 These sit on the membrane of endosomes, in cells that have been previously stimulated by IFN It prevents fusion of the virus membrane with the endosomal membrane so the virus gets trapped in the endosome NOTE: mice and people lacking IFITM3 get more severe 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 This prevents ribosomes from binding to mRNA so NO NEW GENES WILL BE TRANSLATED It also phosphorylates NFkB, which is an important transcription factor that is part of the interferon and inflammatory response
When is PKR activated by cells?
It is an extreme measure and a last resort – only activated when the cell has no other option