2: Interferons Flashcards
Type 1 interferons
Polypeptides secreted from infected cells
Type 1 = IFN alpha & beta
IFN-beta can be secreted by ALL cells and only has one type
IFN-alpha has multiple isotypes
Plasmacytoid dendritic cells are specialised in secreting IFN-alpha
Works via IFNAR receptors
Release is triggered by IRF (interferon releasing factor)
3 functions of interferons:
- Production of ISGs that induce antimicrobial state in infected cell + neighbouring cells
- Modulates INNATE response (promote antigen presentation + NK cells)
- Activates the ADAPTIVE immune response
Type 2 interferons
Type 2 = IFN gamma
Produced by activated T cells and NK cells
Signals through IFNGR receptor
Type 3 interferons
Type 3 = IFN lambda
Important at epithelial surfaces
What are types of immune response to virus
Intrinsic
Innate
Adaptive
Explain intrinsic immunity
ZAP can scan viral RNA for CpG
If it has too many CpG sequences, ZAP binds and targets it for RNA degradation
Virus can no longer replicate
How do we detect viruses? Give examples of receptors
PAMPS detected by PRRs
PRRs:
Rig-like receptors (RLRs)
Toll-like receptors (TLRs)
DNA sensors (cGas)
Differences between the PRRs
TLRs are membrane proteins (i.e. detect things from outside/inside)
RLRs are cytoplasmic (e.g. RigI)
Explain interferon induction with RLRs
RLR (e.g. RigI) detects abnormal nucleic acid in cytoplasm (e.g. ssRNA)
Conformational change in RigI and activates Mavs (on surface of mitochondria)
Mavs signals downstream proteins
Irf3/7 get phosphorylated then dimerise and enter nucleus
Bind to promoter sites on DNA
Induces transcription of IFN beta
Explain interferon induction with TLR
TLR3/7/8 detects foreign nucleic acid (RNA)
Downstream signals lead to phosphorylation of Irf3
Leads to gene expression of Type 1 IFNs
Explain interferon induction with cGAS
DNA viruses (e.g. Herpes) DNA in cytoplasm which shouldnt be there cGAS detects DNA PAMPs cGAS synthesises cGAMP cGAMP binds to STING (membrane of RER) STING phosphorylated -> IRF3 phosphorylated -> expression of Type 1 IFNs
What happens after IFN produced?
IFN-beta is soluble cytokine
Released out of cell
PARACRINE signalling to neighbouring cell
AUTOCRINE signalling to same cell where it was produced
Paracrine signalling -> neighbouring cells produce hundreds of ISGs (antiviral mediators), creating an anti-viral environment within cell
Examples of ISGs
Protein kinase R = inhibits translation
IFITM3 = restricts virus entry through endosomes (e.g. influenza)
Explain MX1/2
Form multimers that wrap around nucleocaspids of incoming viruses
MX1 inhibits influenza
MX2 inhibits HIV
How long does antiviral state last
Maintained for several hours only
After that the ability to respond to IFN is lost due to negative feedback
What turns off responsiveness to IFN
SOCS
Suppresses cytokine signalling
Ways in which viruses evade the IFN response?
- Hide PAMPs
- Interfere with host cell gene expression (so no IFN produced)
- Block IFN cascade by destroying/binding
- Inhibit IFN signalling
- Block action of individual antiviral enzymes induced by IFNs
- Activate SOCS
- Replicate quickly before neighbouring cells respond to IFN
Give 4 examples of ways viruses evade interferon detection.
Hep C: protease cleaves Mavs
Influenza: NS1 binds to Rig-I/RNA complex, prevents activation of signalling pathway. Also enters host nucleus and inhibits translation
Ebola: VP35 inhibits Rig-I, VP24 stop IFN signalling in neighbouring cells
Pox viruses: encode soluble cytokine receptor
Mops up cytokines and stops their action.
Can potentially be used for future immuno-regulatory drug, since it can mop up cytokines in immunopathological diseases like rheumatoid arthritis
What are the consequences of viral infection?
- Virus infects and damages/kills host cells
- Innate immune response kills infected cells
- BUT bystander cells also killed by immune response
Explain how viruses skew the immune response
Many viruses MODULATE the immune response which results in advertant pathology (i.e. we feel ill)
Interferons can be immunopathologic
Explain cytokine storm
Virus replicates -> High IFNs -> Massive release of TNFa + other cytokines
Important: viruses are not being controlled by the IFNs so they replicate and induce more cells to release even more IFNs
Clinical outcome depends on vigour of innate immune system
This varies with age
Typical of Dengue feveer, severe influenza and Ebola
What are the mediators of cytokine storm?
TNF
IFN alpha/beta/lambda
IL-1/6
CCL2
Consequences of cytokine storm?
Endothelial dysfunction (leaky) Inflammatory response (sepsis syndrome) Pulmonary fibrosis
How can IFN-lambda be used for influenza therapy?
IFN-lambda only has receptors on EPITHELIAL cells
whereas IFN-alpha/beta have receptors on ALL cells (including immune cells, leading to immunopathology)
Treatment would induce anti-viral state only in epithelial cells. Hence doesn’t have the side-effects that IFN-alpha/beta would have
Live-attenuated vaccines in the future?
Engineer viruses so that they cannot control IFN
High level of IFN produces rapid immune response
Cells that are deficient in the IFN response pathway (i.e. lack certain proteins like Rig-I) can be used to GROW these attenuated virus strains
How is IFN affected in cancer cells?
Cancer cells are IFN deficient (they dont use the system)
Allows them to avoid apoptosis/immune response and grow uncontrollably
Because of this viruses can replicate very well inside tumours
Anti-cancer viruses that are deficient in counteracting the IFN system are being developed
This means they will be much more specific to cancer cells than normal cells
(Normal cells have IFN system but cancer cells don’t, so virus more likely to survive in cancer cell)
What are 2 types of viruses with genetic drift for which we have vaccines for?
Influenza
Polio
