Microbiology 3: interferon Flashcards
What is the overall strategy for the immune system to defeat viruses?
Inital physical barriers-skin, mucus, etc –intrinsic barrier
Then if they pass that-innate immunity (mins/hours after start)
Then if can pass that-acquired immunity-targetted, specific, but can cause large tissue damage (days/weeks)
and virus can evade or counteract that as well-trouble
What is CpG and ZAP and their relation to basic initial immunity?
Viruses tend to have different amounts of CpG islands on their DNA and can be recognised as foreign
ZAP machinery is a DNA exosome that recognises these CpG content and is chopped us automatically
Viruses with low CpG can pass by
insects dont have ZAP, so insects viruses dont modulate CpG->when infect humans get automatically destroyed
this is non specific, non cellular-nearly like intrinsic immunity
WHat is the definition of interferons?
A generic protein (non specific) produced by the cell to protect itself and stop viral infection
Soluble protein that protect the cell, and spreads to nearby cells -> through receptor cause cells to produce many new genes, to protect themselves againt infection
Antiviral state
What are type I interferons?
Earliest interferons to switch on. INF I receptors on every cell of the body
polypeptides secreted from infected cell
Induce antimicrobial state in that cell and neighbours
Modulate innate immune response to promote Ag presentation to NK
Also help activate acquired immunity
ex: INFa, INFbeta (primary one-any cell can make, any cell has receptor)
Response can happen in epithelium, then if it passes, repeat in fibroblast, of pass that, immune cells can also be induced, producing INFa -> these are professional INF cells
What are TypeI, II and III interferons?
I-INFa, B -> secreted by all cells and bind IFNAR receptor in all tissue
Plasmacytoid dentritic cells pdcs are specialist INFa secreting cells
One gene for INFb, 13/14 isotypes of Alpha
II-INFgamma->produced by activated T cells and NK cells
Receptor IFNGR
Type III-INFlamba
Signal through IL28 and IL10B on epithelial cells-important in very early response
Polymorphisms can determine susceptibility to viruses like HCV or HBV
How does a cell recognises its being infected?
Recognise danger signals, anything that looks foreign-> PAMPs
Pattern recognition receptors in cytosol
Usually sense foreign nucleic Acid (like if it doesnt have the right cap, or if its cytosol, or other)
eg: cytoplasmic RIG-I like receptor, endosomal Tolllike receptor TLR and others (PRR)
What do TLR, RLR and DNA sensors recognise?
TLR-RNA in endosome
RLR-RNA
DNA sensors-DNA
How does RLR work and produce an effector response?
Viral RNA arrive in cytosol -if recognised as foreign (no cap, or something)
RIG and MDA5 can recognise it and form a complex it with MAVS (on mito membrane) -> signals down cascades until phosphorylation of Irf3 or Irf7
phospho-Irf3 dimersises and acts as a TF-> activate transcription of INFB
How does TLR work and produce an effector response?
TLR sit in endosomes
Viruses often use endosomes to enter cells -> and unpack there
TLR3 and TLR7/8 when bind RNA viral activate and signal
TLR3 joins up with RLR pathway and actiavte IrF3
TLR7/8 activates Irf7/8 (always present in Plasmacytoid dentritic cells)-Act as TF and produce INFa
How does DNA sensors and produce an effector response against viruses?
cGAS is enzyme, activates when binds dsDNA in cytosol
When activated, becomes cGAMP
cGAMP recognised by STING-on surface of RER
kind of joins up with MAVS in the Irf3 pathways-> cause activation of type I INF
What in INFB?
small soluble protein-produced by infected cell and signal to itself and neighbours (paracrine and autocrine_
Tells cells via IFNAR receptor -> cause upregulation of interferon stimulated genes-> can be several 100s and are toxic (not produced normally-need to activate only in danger)
How dangerous would it be to not have an INF system?
Pretty much-if not have it ur dead to viral infection, even very mild ones
Child with monogenic inborn in IRF-7 gene-> couldnt fight off flu and had to get through hospital (and still did pretty poorly)
Other person with vaccine (MMR-attenuated) -> got infected with mini-measle -> succubs from vaccines. Mutation in IFNAR2 (1 part of the INF receptors)
Patient mutation with IRF3-Herpes simplex virus (cold sore)-> doing very bad (because of complication-Herpes simplex encephilitis–with no INF working, herpes replicate in CNS)
How doe INFNAR receptors signal downstream and to what>
INFNAR is dimer
Signallin unfoves JCK and STAT phospho and dimerisation-> STAT acts as TF for hundrends on genes, like PKR (inhbits translation), MHC, 2’5’OAS (activate RNAse L that destroys RNA). Mx (inhbits incoming viral genome), ADAR (induce error in viral replication), Serpine (activate proteases), Viperin (inhbits viral budding)
IFITM3- sits in endosome and stop from viral fusing with the membrane to enter the cell (mutations cause more severe influenza)
All these are effective against viruses, but very toxic to your own cell-> stop translation, cut all mRNA, proteases, etc -> needs to be activated very transiently
What are Mx1/2 and how do they help prevent viral infection?
Interferon activated genes
Mx1-binds influenza and stops it from entering the cell/membrane
Mx2-similar but works with HIV
How do interfon response selfregulates to reduce damage?
SOCS-supressors of cytokine signalling-also interferon activated
Will activate at the same time -> downregulate after a while (no detail lol)
