Interferons Flashcards
What do IFNs do?
Binds to specific receptors
&
signals activation of de novo transcription of hundreds of Interferon Stimulated Genes (ISGs)
Describe Type 1 interferons
Polypeptides secreted from infected cells - 3 major functions:
(1) Induce antimicrobial state in infected and neighbouring cells
(2) Modulate innate response to promote Ag presentation and NK
(3) Activate the adaptive I.R
What are the Type 1 interferons?
IFNalpha (IRF-7) & IFNbeta (IRF-3)
IFNb
• one gene for IFNb
• secreted FIRST by ALL cells - as have IFNAR receptors
• production is triggered by IRF-3
IFNa
• 13-14 isotypes of genes for IFNa
• plasmacytoid dendritic cells (pDC) are IFNa-secretin cells
• express IRF-7 constitutively
Describe Type 2 interferons
IFNgamma!
- produced by activated T-cell & NK cells
- signals through a different receptor called IFNGR
Describe Type 3 interferons
IFNlamba!
Signals through receptors IL28R and IL10beta (mainly present on epithelial surfaces)
• so normally expressed during respiratory tract infections and liver infections
• polymorphisms in IFN are associated with IMPROVED outcomes from HCV and HBV with both spontaneous clearance & response to antiviral therapy
How do you differentiate self from non-self?
PAMPs (pathogen associated molecular patterns)
• often sense FOREIGN NUCLEIC ACIDS (e.g. dsRNAs)
via. PRRs (pattern recognition receptors)
• these sit inside cells & detect PAMPs
Explain how PAMPs and PRRs function using examples
(1) RLRs – RIG-I-like Receptors (cytoplasmic)
• bind to Mavs (found on mitochondria) and stimulate signalling and IFN-BETA production
(2) TLRs – Toll-Like Receptors (endosomal)
• found in endosomes and makes IFN-ALPHA
(3) NLRs – NOD (Nucleotide Oligomerisation Domain) Like Receptors (cytoplasmic)
These are all PRRs (as receptors!) which detects PAMPs
What is different about RNA viruses vs. DNA viruses
Single-stranded RNA is a PAMP
BUT
DNA is not:
• DNA viruses are not sensed by RLRs/ TLRs (e.g. dsDNA)
How are DNA viruses tackled instead?
INSTEAD, they are sensed in nucleus by cGAS:
(1) cGAS activates 2nd messenger – cGAMP
(2) cGAMP activates STING (found on ER) –> signalling to nucleus to produce IFN-β
• as triggers SAME downstream messengers that cytoplasmic PAMP dsRNA causes
In what manner can IFN receptors signal?
Paracrine manner!
This is as when activated, IFN receptors are heterodimers of
• IFNAR1 & IFNAR2
AND
are SOLUBLE CYTOKINES
Explain IFN Type 1 Signalling
- IFNAR1 and AR2 dimerise
• & JAK1 and TYK2 cross-phosphorylate - STAT proteins are activated and this activates…
(a) Antiviral response (ISRE).
(b) Inflammatory response (GAS).
(c) Repressors of the inflammatory pathways (GAS).
IFNs induce transcription of HUNDREDS to antiviral mediators
• hence why get a fever & feel sick
Examples of some IFN stimulated genes?
PKR
• inhibits translation
Mx
•inhibits incoming viral genomes
IFITM3
• restricts virus entry through endosomes
miRNAs, ADAR, apoptosis, cell cycle arrest, etc
IFITM3?
IFN Induced Transmembrane Protein 3
Restricts virus entry through endosomes
• by stopping them escaping SO virus broken down by acidic pH
Mx1 & Mx2?
GTPases with a homology to dynamin
Forms multimers to wrap around the nucleocapsids of incoming viruses
• Mx1 - inhibits influenza
• Mx2 - inhibits HIV
What is problematic about the IFN response however?
Does NOT last
• only maintained for a few hours
Ability to respond to IFN is lost gradually due to -VE regulation
• via. SCOS genes (turn IFN response OFF)
SCOS?
Suppressor of Cytokine Signalling
What is viral evasion mediated by/different strategies that can be used evade IFN response
o Virus hides the PAMPS – e.g. inside vesicles
o Interference with host cell gene expression (or protein synthesis)
o Block IFN induction cascades
• NS3/4 protease (HCV)
o Inhibit IFN signalling directly
• NS1 protein (influenza)
o Block action of individual IFN-induced antiviral enzymes
o Activate SOCS
o Replication strategy that is insensitive to IFN
Example of IFN control by viruses - stopping activation?
o Hepatitis C
– NS3/4 proteases
• acts as antagonist to IFN
• cleave Mavs – interferes with induction of IFN
o Influenza
– NS1 protein
• acts as antagonist to IFN
• binds to RIG-I/TRIM25/RNA complex and prevents activation of signalling pathway & prevents nuclear processing of newly induced genes.
Example of IFN control by viruses - stopping signal from getting through?
POX (and herpes) viruses:
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) –> being developed future immune therapies
How does the Ebola virus cycle mechanisms help evade the I.S?
Ebola – 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
Possible uses of IFN as new therapy development?
(1) Live attenuated vaccines
(2) Anti-viral treatments
• soluble cytokines
(3) IFN lambda
• influenza therapeutic drug
(4) Cancer treatment
Explain (1) of the possible new therapy development
(1) Live attenuated vaccines
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
Explain (2) of the possible new therapy development
(2) Anti-viral treatment (soluble cytokines)
IFN can be used be used as treatment (e.g. HCV)
• e.g. vaccinia B18 (Pox virus) mop up IFN so may be useful in autoimmunity
• BUT has unpleasant side-effects
Explain (3) of the possible new therapy development
(3) IFN lamba
• infleunza therapeutic drug
Possibility = IFN λ:
• type 3 IFN – as only expressed on epithelial cells
Not able to signal to immune cells because they don’t have IFN-lambda receptors
Would switch on anti-viral state in epithelium, but wouldn’t get same side effects from immunopathology
Explain (4) of the possible new therapy development
(4) Cancer treatments
o Cancer cells may be deficient in IFN (don’t show good IFN response)
• so if a cancer patient is given a novel virus, the virus can kill the cancer cells whilst the healthy cells produce IFNs to combat the virus
Which answer is NOT true?
Viruses that can’t control the innate I.S well might….
A. be useful as oncolytic agents
B. be difficult to grow in standard cell culture systems
C. be restricted at crossing the host range barrier and unlikely to spark outbreaks in other species
D. be useful as live-attenuated vaccines
E. be highly adapted to their host species
E
Which is TRUE?
Viruses that counteract activation of the innate immune system by:
A. varying their coat protein sequences
B. encoding proteins that cleave or target host immune factors for degradation
C. preventing the loading of peptides by TAP
D. inducing a cytokine storm
E. encoding MHC homologues
B
