What is an interferon?
soluble Polypeptide produced by virus infected cells that signal self and neighboring cells to switch on defence mechanism
What kind of molecule is a Type I interferon?
Polypeptides
(soulouble cytokine)
What is the function of a type one interferon?
- Switch on antimicrobial state in infected and neighbouring cells
- Mudulating immune response by
- Innate: promote Antigen presentation and Natural Killer cells
- Adaptive: Activate the adaptive immune response
Name examples of Type I interferons
IFN beta and IFN alpha
Which cells produce IFN ß?
What is its taget (and where is it present)?
IFN ß is secreted by all (infected) cells and
- bind to IFNAR (Interferon-alpha-Receptor) also present on all cells
Which cells produce IFN alpha?
14 different types Produced by Plasmacytoid dendritic cells
- exepcially involved in immune cell modulation
Which cells produce Type II interferons? Name an example
What do they bind to?
E.g. IFN gamma
- produced by activated T cells and NK cells
- bind to different IFNGR
- regulation/modulation of adaptive immune response
Which cells produce Type III interferons? Name an example
What do they bind to?
E.g. INF lambda
- produced by endothelial cells (not immune cells)
- bind to IL28 and IL10ß receptors
- increase barrier function of epithelial surfaces
Summarist how an Interferon response gets activated
Viral PAMS (Pattern Associated Molecular Patterns) get recogised by PRR (Pattern recognitiion receptors)
–> Set off dowonstream mechanism in cell modulating transcription
–> TF produce Interferon
What are the PAMS that are recognised in Viral infections?
What are thex recognised by?
Different types of viral genome in places where is would normally not be found are recognised
- RNA
- in Cytoplasm: RIG-I like Receptors (RLRs)
- In endosomes: Toll like receptors (TLRs)
- DNA: cGAS
Explain the downstream Mechanism that is set off by activation of RIG-I like Receptors (RLR)
Get activated by ssRNA in the cytoplasm
- RLR foreign genome and
- actiate MAVS (mitochondrial antiviral signaling protein)
- leads to activation of downstream kinase cascasde leading to
- phosphorylation of Irf3
- Irf3 phosphoarylation causes dimerisation and activation of the Transcriptionfactor
- Expression of Interferon gene
Explain the downstream Mechanism that is set off by activation of TLRs (Toll-Like Receptors)
TLRs= sense RNA in endosomes (mainly on dendritic cells)
- Activation of Tlr3
- Trif
- Irf3
- Activation of TLR 7+8 (expecially on dendritic cells)
- Activation of Myd88
- NF-kb and Irf7
Activation of Transcription Factors lead to INF Type I production!
Explain the effects of activation of cGAS
cGas are activated by dsDNA in the cytoplasm leading to
- activation of cGAMP which
- activate STING
- STING (similar to MAVS) activate Irf3 (interferon regulatory factor 3)
- induced expression of type I IFN
What are the effects of IFN binding to a cell?
Leading to: activation of downstream mechanism and induces transcription of 100s of antiviral mediators
How does INF binding to INFAR lead to transcription of antiviral mediators?
- INF binding caues dimerisation of INFAR
- Via adaptor protein JAK –> phosphorylation of STAT
- STAT phosphorylation causes STAT dimerisation which forms the Transcription factor
- migrates to nucleus and causes stimmulation of production of many genes
- STAT phosphorylation causes STAT dimerisation which forms the Transcription factor
What are the effects of expression of the ISG (interferon stimmulated Geners?
Many hundret genes expressed–> widely varied antiviral effects e.g.
- inhibition of (viral and host) translation (Protein Kinase R)
- Destruction of ssRNA (via RNAse L) (host and viral)
- Inhibition of incoming viral genome (Mx)
- Errors during viral replication (ADAR)
- Protease Activation
- Inhibition of viral budding
- MANY RESPONSES THAT ARE TOXIC FOR CELL AND VIRUS
What kind of protein is IFITM3?
What does it cause?
IFITM3= ISG (interferon stimulated gene)
- Restict the virus entry through the endosome (inhibits endosome budding)
Explain the role of Mx1 and Mx2 in antiviral defence
Mx1+2 are ISG (INF stimmulated genes) causing
- multimer formation that wraps around and inhibits nucleocapsids of incoming viruses
Explain why and how INF response is regulated
It can only be obtained for several hours because
- of strong, toxic effects of INF on the cells
- Turned off via negative regulation
- SOCS (suppressor of cytokine signalling) genes turn off the response
Explain why it is important for Viruses to evade the INF response
Because it is so powerful and otherwise Viruses would not have a chance to be virulent
What are general mechanisms by which virused can evade the INF system?
- Avoid detection by hiding the PAMP
- Interfere globally with host cell gene expression and/or protein synthesis
- Interfere directly with IFN
- Block IFN induction cascades by destroying or binding
- Inhibit IFN signalling
- Block the action of individual IFN induced antiviral enzymes
- End IFN response by Activate SOCS
- Replication strategy that is insensitive to IFN (e.g. very fast)
Explain how Hepatitis C can evade the IFN response
- Hep C interferes with downstream mechanism that would cause IFN activation
NS3/4 protease acts as antagonist to interferon induction by cleaving MAVS
Explain how Influenza can evade the IFN repsonse
- NS1 inhibits IFN activation by
- antagonisingby binding to RIG-I /TRIM25/RNA complex and preventing activation of signalling pathway
- and also prevents nuclear processing of newly induced genes (inhibits some newly formed genes that are needed for production of IFNß)
Explain how POX viruses and Herpes evade the IFN pathway
Is a large DNA virus
- have accessory genes that modify host immune system
- e.g. expression of soluble cytokine receptors
