MM5 Virus immunomodulation Flashcards
What is immunomodulation?
Modification of the immune response or the functioning of the immune system by the action of an immunomodulator
Why study viral immunomodulators?
Can help us to develop effective drugs
Can help us to develop live attenuated vaccines. We can delete genes which we know encode immunomodulators
What are the complement immunomodulators?
VCP= Vaccinia complement control protein
Influenza M1 matrix protein
SPICE= Small pox inhibitor of complement enzymes
What is VCP and what does it do?
VCP is vaccinia complement control protein
It is able to inhibit C3b and C4b which can protect the virus from the classical and alternative complement pathways
What is SPICE and what does it do?
Encoded by Variola
Small Pox Inhibitor of Complement Enzymes
It is more potent than VCP, even though they only differ by 11 amino acids
It can inhibit C3b
What is M1?
Matrix protein 1
Influenza A
It can prevent C1q from interacting with IgG
This is able to prevent the classical complement pathway
What immunomodulators target apoptosis?
N1 of Vaccinia
What three proteins have a Bcl-2 like structure?
N1, A52 and B14 of Vaccinia virus
Which proteins of Vaccinia virus have a Bcl-2 like structure?
N1, A52 and B14
What is the function of N1?
To inhibit apoptosis
What are the functions of A52 and B14?
Their function is to prevent NF-kB signalling
How can N1 inhibit apoptosis but A52 and B14 cannot?
As A52 and B14 lack the hydrophobic surface groove which is able to bind BH3 domains of pro-apoptotic molecules
How does B14 interrupt with NF-kB signalling?
It is able to prevent the phosphorylation and degradation of IkB which inhibits NF-kB
What are the Bcl-2 family of proteins?
These proteins are either pro-apoptotic or anti-apoptotic
How do anti-apoptotic proteins belonging to the Bcl-2 family prevent apoptosis?
They bind to the BH3 domain on pro-apoptotic molecules such as BH3-only proteins. They are gatekeepers of the mitochondria and prevent the release of cytochrome c
How is it believed A52 and B14 were acquired?
Through pirating of host genes
Obtained host Bcl-2 gene
Through gene duplication the sequence has diverged but the overall Bcl-2 structure has remained
Has evolved different functions e.g. can interfere with NF-kB signalling
How can N1 prevent apoptosis?
Possesses a hydrophobic surface groove which can bind the BH3 domain of pro-apoptotic molecules
Virus antagonism of TLR signalling via NF-kB? Which viral immunomodulators interfere with TLR signalling?
NS3/4A of hepatitis C is able to cleave TRIF which is an important adaptor required for TLR3 signalling
Vaccinia B14 and A52 are able to interfere with NF-kB signalling
Virus inhibition of induction of other signalling pathways?
NS3/4A of hepatitis C is able to cleave MAVS/Cardif and interfere with RIG-I/MDA-5 signalling
NS3 is able to prevent TBK1 interacting with IRF-3. This prevents IRF-3 phosphorylation and activation
NS1 of Influenza A is able to inhibit RIG-I
NS1 of influenza A can do what?
Prevent 3’ processing of cellular mRNAs
Able to inhibit RIG-I
What does NS3/4A of HCV do?
It is able to cleave MAVS/Cardif to interfere with MDA-5/RIG-I signalling
It is able to cleave TRIF which is an essential adaptor for TLR3 signalling
NS3 can prevent the interaction of TBK1 with IRF-3
Virus antagonism of IFN signalling?
VP24 of Ebola can prevent the nuclear accumulation of tyrosine phosphorylated STAT-1
VH1 phosphatase of Vaccinia can deactivate tyrosine phosphorylated STAT-1
What does VP24 of Ebola do?
It prevents nuclear accumulation of tyrosine phosphorylated STAT-1
What does VH1 phosphatase of Vaccinia do?
Can deactivate activated STAT-1 by dephosphorylation it
Intercepting interferons?
Vaccinia B18R and B8R can intercept interferons
B18R?
This is akin to a type I interferon receptor
Can bind to type I interferons
B8R?
Akin to a type II interferon receptor
Can bind type II interferons
Which virus can inhibit TAP and how?
Herpes virus can inhibit TAP via UL49.5
Inhibition of TAP leads to?
Leads to downregulation of MHC-I on the cell surface
How can viruses reduce competition with cellular functions?
NS1 of influenza can prevent 3’ processing of cellular RNAs so they remain in the nucleus
Influenza cap snatching mechanism
Polio virus 2A protease is able to cleave eIF4G and prevent cap dependent translation of cellular mRNAs
How can vaccinia virus prevent the cell reacting to the presence of dsRNA?
E3 is able to binds dsRNA
K3 mimics eIF2-a and can directly bind to activated PKR, it acts as a decoy substrate
Why can vaccinia K3 be referred to as a decoy substrate?
As it can mimic host eIF2-a
How does vaccinia gain all the genes for immunomodulation?
Gene pirating
What happens after gene pirating?
Gene accordion- gene duplication
