Interferon Flashcards
What are the four major barriers for viruses
• anatomical and chemical barriers (skin, mucus, stomach acid)
• intrinsic immunity
(INF, Apoptosis, Autophagy) => requires no previous contact
• innate immunity
• acquired immunity
Intrinsic response
• directly create antiviral state in infected cells (or death)
• recognise infection => signal to neighbouring cells
• prime cellular immunity
Lindenmanns experiments
Cells incubated with heat inactivated influenza virus => supernatant (fluid without cells) => give to new cells, add virus => no virus replication
Clinical application of IFN
• Hepatitis B/ Hepatitis C
• Papilloma virus
• newly emerging viruses (must be given early!)
=> but many side effects
Side effects of IFN
If too late IFN makes infection worse
General side effects:
Fever, chills, nausea, malaise
=> Flu like symptoms
PAMPs
Non self patterns unique to infected cells
=> dsRNA
=> cytoplasmic DNA
Sensors for IFN
PRRs (pattern recognition receptors
RIG-I and mda5 for ds RNA
cGAS for DNA
Signaling cascade PAMP recognition RNA viruses
receptors (RIG-I, mda5)
Adaptor Mavs at Mt
=> activates Kinases (TBF, IkK) that phosphorylate cytosolic TFs => Irf3 &7 => upon activation enter nucleus and activate interferon protein transcription
Signaling cascade PAMP recognition DNA viruses
DNA in cytosol
cGAS receptor binds DNA
Adaptor protein on membrane (e.g. ER) = STING (stimulator of IFN gamma)
activates signaling kinases (TBK1/IkK)
Phosphorylate TFs (IRF3, NFkB)
Interferon receptor
IFNAR1/2
works like brassinosteroid/ssp receptors
Heterodimer of 2 subunits (IFN alpha recepror 1 &2) that are receptorkinases
Signaling kinases => Janus kinase 1 (Jak1) and Tyrosine kinase 2 (Tyk2)
=> ligand increases affinity
=> activation of kinases
IFN signaling
IFN binds to receptor
Jak1/Tyk2 become activated
phosphorylate Adaptor/TF STAT1/STAT2 complex, upon activation this binds IRF9 (TF) which enables it to enter the nucleus and activate transcription of IFN-induced genes (interferon stimulated genes ISGs)
What are virus responses to IFN?
Inhibition of production
Prevention of binding
Inhibition of signaling
Which viruses can interfere with IFN?
All viruses must to some extent interfere, some encode multiple IFN antagonists to inhibit different stages of IFN system (e.g. Zika, Influenza)
The more efficient the inhibition, the more it can replicate
How can viruses interfere with IFN?
Inhibition of receptors (RIG-I) => proteins that bind PAMPs => like buffer
Degradation of STAT2 => Zika has protein that ubiquinates STAT2 => degradation => but not in mice!
Life attenuated vaccines
E.g. IFN inhibition mutants
IFN-antagonism can determine…
host tropism
Antiviral proteins of IFN
Some specific to some viruses
IFITMs
Mx
PKR
Theterin
TRIM21
IFITM
IFN-inducible transmembrane protein
Prevents fusion of viral membrane with cell membrane after viral attachment (blocks entry for viruses that enter by endocytosis)
SNP mutation of IFITM3
looses antiviral function => inactive delta21
SNP mutation
=> these people more suceptible for infection
=> human genetic determinant for risk groups
MxA
Myxovirus resistance protein A
Influenza (RNA virus) replicates in nucleus
MxA makes rings to bind to viral RNA, stops it from entering nucleus
PKR
Protein kinase R
=> all viruses need cellular machinery
Not active, but present in cell
=> two signals IFN leads to upregulation, PAMP leads to activation
=> phosphorylates eIF2alpha (eukaryotic initiation factor alpha) which jnactivates it
=> required to bring in tRNA => no translation without it
=> no prot production = cell death
Tetherin
prevents viral budding
sits in membrane
holds on to fully enveloped virus particles
=> keep them to cell
=> or take them in and digest them in emdosomes
TRIM21
links innate and adaptive immunity
=> danger sensor
=> antibody binding
ubiquitinates virion (E3 ubiquitinase activity) for degradation
How can viruses inhibit antiviral proteins?
Example PKR => protein kinase R (RNA-activated) (essential, have to try to antagonise this)
NS1 of influenza binds to dsRNA => second signal for PKR => remains active
Herpes phosphatase => cuts off phosphate that PKR attaches to eIF2alpha
Pox virus produces protein (K3L) very similar to eIF2alpha, that gets phosphorylated instead
evolutionary arms race => faster mutation rate means selection pressure
