Viral Evasion of Immune Response Flashcards
Do we need an innate response?
Yes, its major role is limiting initial infection to a manageable level
Adaptive system isn’t quick enough
What is innate immunity?
Mechanical barriers
Cytokine-mediated responses (IFN, TNF, IL-1, etc)
Cell mediated (NK cells)
What do the following cytokines do?
IFN-alpha/beta
TNF-alpha
IL-1
IL-12
IFN-alpha/beta - fever, direct antiviral effects, activate NK cells
TNF-alpha - fever, shock
IL-1 - fever, IL-6 production
IL-12 - activates NK cells, signals adaptive immune response
What are interferons?
Interferons are protein components of animal cells which are synthesised and excreted under a variety of stimuli and make other cells of the same species incapable of replicating virus
What was Issac and Linderman’s Discovery in 1957?
Cells + heat inactivated influenza virus
Incubate overnight
Discard cells and transfer supernatant onto new cells
Incubate overnight
Add live virus
-> no infection
What is the antiviral action of IFN?
IFN-gamma is produced by the immune response
IFN-alpha/beta is produced by the viral infected cell
Both IFN forms attach itself to surface of virus infected cell + neighbouring uninfected cells
IFN signals to uninfected cells and induces ‘antiviral state’ that limits viral replication
How would viruses evade innate immune defences?
They need to overcome the initial anti-viral response
Viral proteins inhibit the signalling cascades emanating from the PRRs
How does detection of viral PAMPs activate the IFN response?
PRRs active > signalling pathways > transcription of interferon-regulatory factor 3 (IRF3), IRF7, and nuclear factor kappa-B (NKkappaB) that leads to the expression of IFN-beta
IFN-beta expresses numerous IFN-stimulated genes (ISGs) > initiates antiviral effector programme
Amplification + regulation of IFN response:
- RIG-I (retinoic-acid-inducible gene I)
- MDA5 (melanoma differentiation-associatedgene 5)
-DAI (DNA-dependent activator of IRFs)
- Some microRNAs
- TRIM (tripartite motif-containing) family of proteins
What are IFN classifications?
Type I (includes IFN-alpha and IFN-beta)
Mainly involved in innate innume response against viral infection
Type II (includes IFN-gamma)
Type III
IFN Type I
PRRs recognise pathogens > type 1 IFNs are produced
Immune cells produce IFN-alpha + IFN-beta + other cytokines > trigger antiviral responses by binding to common transmembrane receptor, Interferon alpha receptor (IFNAR) > ligand binding activates both subunits and results in dimerisation > autophosphorylation rearranges dimer > downstream proteins activated (ie Signal Transducer and Activator of Transcription (STATs), MAPK pathway, PI3K and mTOR pathway)
What viruses activate which IFN producing pathway?
RNA viruses:
Virus > activate MAVS > activates RIG-1 > TBK1 > IRF + NFkappaB > translocate to nucleus > stimulate production of IFN-1 and other cytokines
DNA viruses:
Virus > activate STING > activates RIG-1 > TBK1 > IRF + NFkappaB > translocate to nucleus > stimulate production of IFN-1 and other cytokines
IFNAR structure
Consists of two subunits: IFNAR1 and IFNAR2
IFNAR1 is associated with tyrosine kinase 2 (TYK2)
IFNAR2 is associated with JAK1
JAK-STAT signaling pathway when activated by IFN-alpha/beta
Ligand binding + dimerisation > Jak on each half cross-phosphorylates the other > activated Jaks phosphorylate tyrosine kinase on receptor > STAT proteins dock to phosphotyrosine molecules > signal is sent to IRF9 molecule which is activated > STAT1 + 2 are phosphorylated > STATs dissociate > STATs dimerise via SH2 domains > STAT dimer associates with IRF9 (bcomes ISGF3) > translocate to nucleus > binds to DNA binding domain > associates with IS Response Element (ISRE) > activates ISGs > initiates transcription
Phosphorylated STAT 1 can also form a homodimer that can bind IFN-gamma activated site to promote transcription
MAPK cascade
Type I IFNs can also activate this pathway
Ligand binds to receptor tyrosine kinase > receptor dimerises and transphosphorylates > phosphorylated tyrosine residue binds Grb2 > binds SOS > activates RAS (binds GTP) > activates MAPKKK > phosphorylates MAPKK > phosphorylates MAPK > MAPK can enter nucleus > activates transcription factor > upregulates genes involved in cell survival and cell proliferation
PI3K and mTOR pathway
Ligand binds to receptor tyrosine kinase > receptor dimerises and transphosphorylates > PI3K is activated > PI3K phosphrylates PIP2 into PIP3 > PIP3 activates Akt > Akt activates mTOR > inhibits apoptosis thereby promoting cell survival + cell growth + cell cycle progression + anabolic effects
PTEN can inhibit PI3K
