Microbiology 2 - Interferons and how viruses evade them Flashcards
What is the most common cause of sporadic encephalitis in the western world?
Herpes Simplex Encephalitis (HSE) - most common in childhood
Affects healthy individuals on primary infection with HSV-1
HSE is associated with inborn errors in genes - give some examples and what do they do
e.g. TLR3, UNC93B1, TRIF, TRAF3, TBK1, IRF3
These genes are all linked by a common pathway
Errors in these genes impair intrinsic CNS IFN a/B response to HSV infection
What do ZAP and CpG do?
ZAP determines if Nucleic Acid is ours or viruses - if there are too many C=G nucleotides, ZAP targets and degrades the Nucleic acid
What is an interferon
Transferable, soluble cytokine, that binds to specific repeaters and signals activation of de novo transcription of Interferon Stimulated Genes (ISGs) - these are antiviral
Also has SEs like fever and inflammation
Type 1 IFNs are secreted from infected cells. List 3 of their functions
- Induce antimicrobial state in infected and neighbouring cells
- Modulate innate response to promote Ag presentation and NK
- Activate adaptive immune response
What are the main producers of Type 1 IFNs
Plasmacytoid Dendritic Cells (PDCs)
What are the type 1 IFNs
IFN alpha and beta
IFNb secreted by all cells
IFNAR receptors on ALL tissues
Which regulatory factor triggers production of IFNb
IRF-3
Which regulatory factor is important for IFN-a secretion
IRF-7
What is a difference between IFN a vs IFN b
There is only 1 IFN-b, but 13-14 isotopes of IFN-a
What type of IFN is IFN-gamma and what produces it
It is a type 2 IFN
It is produced by activated T cells and NK cells - signalled through receptor IFNGR
What type of IFN is IFN-lambda and where is it mainly present?
What is it signalled by?
Type 3 IFN - signalled by IL28R and IL10-b
Mainly present on epithelial cells - so it doesn’t work on immune cells
Polymorphisms in IFN-lambda are associated with improved outcome from which viruses?
HCV and HBV
How do cells differentiate self from non-self
They have PRRs that recognise PAMPs
Often sensing foreign nucleic acid
Name 3 types of PRRs
- Cytoplasmic RIG-1 like receptors (RLRs)
- Endosomal Toll like receptors (TLRs)
- Cytoplasmic nucleotide oligomerization domain receptors NLRs
Where are TLRs located
Membrane proteins - on the membrane
They can be on the cell surface or endosomal
Where are RLRs and DNA sensors (e.g. cGAS) located
Cytoplasm
Explain how the RIG-I pathway can induce IFN-b
TLR works in a similar way but not through MAVS
- Viral RNA recognised by RIG-I
- Receptor changes shape and interacts with MAVS (sits on mitochondria)
- MAVS activates path that phosphorylates IRF-3
- IRF-3 enters nucleus and stimulates promotor of IFN-b gene
RNA is recognised by which PRRs?
TLR and RIG-I
Explain how viral DNA is sensed and pathways triggered as a result
- Any DNA in the cytoplasm is aberrant and a PAMP, which is sensed by cGAS
- Causes production of cGAMP
- This is detected by STING and binds to it (STING sits on organelle membrane)
- Phosphorylation and dimerisation of IRF-3
- IFN-b promoted
How do IFNs induce antiviral actions
- They are secreted by the infected cell
- They then bind receptors on neighbours (paracrine) or same cell (autocrine) - IFNAR-1 and dimerisation occurs due to phosphorylation events
- This activates ISGs
- Giving off antiviral signals
Name 7 Interferon Stimulated Genes (ISGs) and how they work
- PKR - inhibits translation by reducing ribosome recycling
- 2’5OAS - activates RNAse L that destroys ss RNA (including cells own RNA)
- Mx - inhibit incoming viral genomes - GTPase with homology to dynamin
- ADAR - induces errors during viral replication
- Serpine - activates proteases
- Viperin - inhibits viral budding
- IFITM3 - restricts viral entry via endosomes - makes endosomal membrane very rigid (lack of IFITM3 = higher risk of influenza)
What is Mx. How many forms are there and what is special about it
Mx = ISG
Mx 1 + 2 (cytoplasm) form multimers - wrap around nucleocapsids of incoming viruses (then inhibit transcription, replication, nuclear entry)
Mx 1 - inhibits influenza
Mx 2- inhibits HIV
Why does the antiviral state not last
It is only maintained for a few hours - the ability to respond to IFN is lost (negative regulation) - due to SOCS (suppressor of cytokine signalling) genes
Cytokines cause inflammation and also cause collateral damage
7 ways in which viruses can evade the IFN response
- Avoid detection by hiding the PAMP
- Interfere globally with host cells gene expression and/or protein synthesis
- Block IFN induction cascades by destroying or binding
- Block action of individual IFN induced enzymes
- Inhibit IFN signalling
- Activate SOCS
- Replicate in ways that are insensitive to IFN
2 ways in which viruses controlling/stopping IFN activation
- Hep. C virus (HCV) - NS3/4 protease cleaves MAVS so less/no IFN
- Influenza - NS1 binds to RIG-I/TRIM23/RNA complex which prevents activation of the signalling pathway - also preventing nuclear processing of newly induced genes (e.g. IFN-b)
What type of viruses are POX and herpes viruses
Large DNA viruses
How do Pox viruses prevent the signal getting through?
The technique is being researched to treat RA in future
More than half the genome of Pox Is accessory genes used to modify the immune response
They encode soluble cytokine receptors that are false –> bind to cytokines so cytokines don’t bind to the proper receptors
What immune evasion mechanisms does the Ebola virus have
Ebola virus encodes VP35 and 24
VP35 - blocks RLR signalling
VP24 - blocks IFN-R signalling on neighbour cells - ISGs not stimulated
How can viruses cause immunopathology
They modulate an immune response but excess IFN production causes inadvertent pathology (e.g. cytokine storm)
Too much IFN can be immunopathologic (e.g. 100x more IFN needed for IL-6 than Mx -> IL-6 has more inflammatory effects on the body)
Explain the features of a cytokine storm
Uncontrolled viral replication
Induces large IFN, TNFa and IL-1/6
(Clinical outcome depends on vigour of innate immune system - i.e. worse in young people)
Which viral infections is cytokine storm typical of
Dengue haemorrhagic fever, severe influenza infections, ebole
What are the effects of a cytokine storm
Endothelial dysfunction
Inflammatory responses
Pulmonary fibrosis
Give an example of IFN use as an antiviral
Used for HCV (not anymore - Pegylated IFN often used with ribavirin)
Not used as associated with unpleasant SEs
How can viruses be used as oncolytic treatment
- Viruses deficient in IFN control attenuated with IFN competent cells
- Viruses therefore induce high IFN levels (IFN acts as an adjuvant to recruit useful immune cells)
- Cancer cells are naturally IFN deficient - so they will not be able to survive when the virus is injected
Essentially, viruses that can’t control IFN can be used as a new type of live attenuated vaccine
