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
Name a family of genes that suppress the cytokine signalling and turn off the response.
State some mechanisms of viral evasion of the IFN response.
Avoid detection by hiding the PAMP Interfere globally with host cell gene expression and/or protein synthesis Block IFN induction cascades Inhibit IFN signalling Activate SOCS Replication strategy that is insensitive to IFN
Explain how hepatitis C controls the interferon response.
NS3/4 This is a protease that cleaves MAVS MAVS is important in detecting Hep C through the RIG-I pathway So Hep C is not detected
Explain how influenza controls the interferon response.
NS1 Acts an antagonist to interferon induction by binding to the RIG-I/TRIM25/RNA complex and preventing activation of the signalling pathway It also prevents nuclear processing of newly induced genes NS1 also migrates to the nucleus where it prevents the export of newly synthesised genes
What type of virus are Pox and Herpes viruses?
Large DNA viruses
- •PKR Protein Kinase R: inhibits translation
- •2’5’OAS: activates RNAse L that destroys ss RNA
- •Mx: inhibits incoming viral genomes
- •ADAR : induces errors during viral replication
- •Serpine: activates proteases
- •Viperin: inhibits viral budding
Explain why the Antiviral state does not last
•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.