What are type 1 interferons?
polypeptides with 3 functions:
- Induce antimicrobial state (local and adjacent)
- Modulate innate response – promote Ag presentation (and NK) but inhibit pro-inflammation
- Activate adaptive immune response
type 1 - IFNa (IRF-7) and IFNb (IRF-3):
- IFNb is secreted first and by ALL cells (IFNAR is the receptor) and production is induced by IRF-3 - One gene for IFNb
- Plasmacytoid dendritic cells (pDC) = IFNa-secreting cells and express IRF-7 constitutively
What are type 2 interferons?
IFN(gamma):
- Produced by activated T-cells and NK cells
- Signals through a different receptor called IFNGR
What are type 3 interferons?
INF(lambda):
- Signals through receptors IL28R and IL10b (mainly present on epithelial surfaces)
- normally expressed during respiratory tract infections and liver infections
- Polymorphisms in IFN(lambda) are associated with IMPROVED outcomes from HCV and HBV with both spontaneous clearance and response to antiviral therapy
How do errors in certain genes cause increased fever and/or death?
- IRF-1 genes – results in increased interferon production meaning they feel very ill
- IFNAR2 gene – this is an interferon synthesis receptor gene that is faulty so they don’t make interferon
- IRF-3 gene – important in the stimulatory pathway to create interferon
What is herpes simplex encephalitis?
common cause of sporadic encephalitis in western world (common in childhood)
Inborn gene errors implicated in HSE – TLR3, UNC93B1, TRIF, TRAF3, TBK1, IRF3
People that get infected with HSE normally have an effective INF response but sick HSE people may have inborn errors in the activation of this pathway
What are PAMPs?
Pathogen Associated Molecular Patterns – often sense foreign nucleic acids (e.g. dsRNA)
What are PRRs?
Pattern Recognition Receptors – these sit inside cells and detect PAMPs:
- RLRs – RIG-I-like Receptors (cytoplasmic) - Bind to Mavs (found on mitochondria) and stimulate signalling and IFN-b production
- TLRs – Toll-Like Receptors (endosomal) - Found in endosomes and makes IFNa
Describe the process of interferon induction
The virus comes in and it makes some RNA -> RNA will be recognised by one of the PRPs (RIG-I or Mda-5) that sits in the cytoplasm -> change shape and unfold, to interact with a second molecule sitting on the mitochondria (Mavs – mitochondrial activated virus signaller) -> Mavs sends a signal, which ends up phosphorylating IRF-3 -> IFR-3 moves into the nucleus and attaches to the promoter of the IFN-beta gene -> drives new synthesis of mRNA for IFN-beta, therefore new IFN-beta molecules are made and the response begins.
What does cGAS do?
enzyme that detects dsDNA in the cytoplasm and promotes production of cGAMP - cGAMP then passes to STING protein found on the ER and this triggers the same downstream messengers that cytoplasmic PAMP dsRNA causes
What is IFITM3?
IFN-induced transmembrane protein 3- an ISG. The gene products sit on the membrane of endosomes, in cells that have been stimulated with IFN.
When IFITM3 is overexpressed, the membranes of the endosomes become very rigid, and the virus cannot escape into the cell. The normal entry for flu virus into cells is to come in through the endosome, and to inject its DNA into the nucleus
What is Mx1?
sits in the cytoplasm of cells, and traps viruses just as they are releasing their nucleic acid (this nucleic acid is traversing around the cytoplasm)
effective against flu, rabdoviruses and other viruses. Mx1 attacks these viruses if they enter the cell
What is Mx2?
homologue of Mx1
This seems to be important in controlling HIV. HIV needs to inject its RNA genome into the nucleus of the cell. If Mx2 is upregulated, this is prevented.
What is viral evasion mediated by?
H - Virus hides the PAMPS – e.g. inside vesicles
I - Interference with host cell gene expression (or protein synthesis)
B - Block IFN induction cascades
I - Inhibit IFN signalling directly
B - Block action of individual IFN-induced antiviral enzymes
A - Activate SOCS
R - Replication that is insensitive to IFN
How does hepatitis c evade the IFR response?
NS3/4 proteases – cleave Mavs – Interferes with induction of IFN
How does influenza evade the IFR response?
NS1 protein – binds to RIG-I/TRIM25/RNA complex and prevents activation of signalling pathway and prevents nuclear processing of newly induced genes
How does POX (and herpes) evade the IFR response?
More than half of the pox virus genome is comprised of accessory genes that can modify the immune responses
Pox viruses encode soluble cytokine receptors (vaccinia virus B18) -> future immune therapies
How does ebola evade the IFR response?
evades the IFN response by VP35, VP24 and VP30:
- VP35 – blocks RIG-I Like complexes and RNAi expression
- VP30 – blocks RNAi expression
- VP24 – directly blocks IFN signalling
What happens in a cytokine storm?
virus replication than induces high IFN accompanied by a massive surge in TNFa and others
Differences in the clinical outcome may vary with age and health – so the less ill you get (healthier), paradoxically, the more severe the clinical outcome as you’re better at producing IFN.
- E.G. Dengue haemorrhagic fever, Ebola and severe influenza
Cytokines involved – TNF, IFN(a/b), IFN(gamma), IL-1, IL-6, CCL2 -> Result in endothelial dysfunction, inflammatory responses and pulmonary fibrosis
How can interferons be used as anti-viral treatment?
IFN can be used as a treatment (e.g. HCV) but has unpleasant side effects
- IFN(lambda) - influenza therapeutic drug:
> IFN(lambda) only stimulates an anti-viral state and
NOT an immune response and immunopathology
How are live attenuated vaccines created and used?
- Creation – viruses deficient in control of IFN are attenuated in IFN competent cells
Cells naturally or engineered to be deficient in IFN response can be used to grow these attenuated virus strains
Use – high IFN levels they induce can recruit useful immune cells with IFN acting as an adjuvant
