MM5 Virus immunomodulation

Question 1

What is immunomodulation?

Answer 1

Modification of the immune response or the functioning of the immune system by the action of an immunomodulator

Question 2

Why study viral immunomodulators?

Answer 2

Can help us to develop effective drugs

Can help us to develop live attenuated vaccines. We can delete genes which we know encode immunomodulators

Question 3

What are the complement immunomodulators?

Answer 3

VCP= Vaccinia complement control protein
Influenza M1 matrix protein
SPICE= Small pox inhibitor of complement enzymes

Question 4

What is VCP and what does it do?

Answer 4

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

Question 5

What is SPICE and what does it do?

Answer 5

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

Question 6

What is M1?

Answer 6

Matrix protein 1
Influenza A
It can prevent C1q from interacting with IgG
This is able to prevent the classical complement pathway

Question 7

What immunomodulators target apoptosis?

Answer 7

N1 of Vaccinia

Question 8

What three proteins have a Bcl-2 like structure?

Answer 8

N1, A52 and B14 of Vaccinia virus

Question 9

Which proteins of Vaccinia virus have a Bcl-2 like structure?

Answer 9

N1, A52 and B14

Question 10

What is the function of N1?

Answer 10

To inhibit apoptosis

Question 11

What are the functions of A52 and B14?

Answer 11

Their function is to prevent NF-kB signalling

Question 12

How can N1 inhibit apoptosis but A52 and B14 cannot?

Answer 12

As A52 and B14 lack the hydrophobic surface groove which is able to bind BH3 domains of pro-apoptotic molecules

Question 13

How does B14 interrupt with NF-kB signalling?

Answer 13

It is able to prevent the phosphorylation and degradation of IkB which inhibits NF-kB

Question 14

What are the Bcl-2 family of proteins?

Answer 14

These proteins are either pro-apoptotic or anti-apoptotic

Question 15

How do anti-apoptotic proteins belonging to the Bcl-2 family prevent apoptosis?

Answer 15

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

Question 16

How is it believed A52 and B14 were acquired?

Answer 16

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

Question 17

How can N1 prevent apoptosis?

Answer 17

Possesses a hydrophobic surface groove which can bind the BH3 domain of pro-apoptotic molecules

Question 18

Virus antagonism of TLR signalling via NF-kB? Which viral immunomodulators interfere with TLR signalling?

Answer 18

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

Question 19

Virus inhibition of induction of other signalling pathways?

Answer 19

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

Question 20

NS1 of influenza A can do what?

Answer 20

Prevent 3’ processing of cellular mRNAs

Able to inhibit RIG-I

Question 21

What does NS3/4A of HCV do?

Answer 21

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

Question 22

Virus antagonism of IFN signalling?

Answer 22

VP24 of Ebola can prevent the nuclear accumulation of tyrosine phosphorylated STAT-1
VH1 phosphatase of Vaccinia can deactivate tyrosine phosphorylated STAT-1

Question 23

What does VP24 of Ebola do?

Answer 23

It prevents nuclear accumulation of tyrosine phosphorylated STAT-1

Question 24

What does VH1 phosphatase of Vaccinia do?

Answer 24

Can deactivate activated STAT-1 by dephosphorylation it

Question 25

Intercepting interferons?

Answer 25

Vaccinia B18R and B8R can intercept interferons

Question 26

B18R?

Answer 26

This is akin to a type I interferon receptor

Can bind to type I interferons

Question 27

B8R?

Answer 27

Akin to a type II interferon receptor

Can bind type II interferons

Question 28

Which virus can inhibit TAP and how?

Answer 28

Herpes virus can inhibit TAP via UL49.5

Question 29

Inhibition of TAP leads to?

Answer 29

Leads to downregulation of MHC-I on the cell surface

Question 30

How can viruses reduce competition with cellular functions?

Answer 30

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

Question 31

How can vaccinia virus prevent the cell reacting to the presence of dsRNA?

Answer 31

E3 is able to binds dsRNA

K3 mimics eIF2-a and can directly bind to activated PKR, it acts as a decoy substrate

Question 32

Why can vaccinia K3 be referred to as a decoy substrate?

Answer 32

As it can mimic host eIF2-a

Question 33

How does vaccinia gain all the genes for immunomodulation?

Answer 33

Gene pirating

Question 34

What happens after gene pirating?

Answer 34

Gene accordion- gene duplication