Interferon

Question 1

What is the most common cause of sporadic encephalitis worldwide? Which subset of the population is this most common in?

Answer 1

Herpes simplex encephalitis

Children: affecting previously healthy individuals on primary infection with HSV-1

Question 2

What is interferon?

Answer 2

Transferrable factor produced when cells are exposed to virus

Question 3

What is the effect of interferon binding to interferon receptors on cells?

Answer 3

Signals the de novo transcription of 100s of interferon stimulated genes (ISG)

Question 4

What are the 3 functions of type I interferons?

Answer 4

Induce antimicrobial state in infected + neighbouring cells
Modulate innate immune response to promote antigen presentation + NK cells
Activate the adaptive immune response

Question 5

What are the type I interferons?

Answer 5

IFN alpha + IFN beta

Question 6

What is the first interferon to be produced in a viral infection?
Which cells produce this?

Answer 6

IFN beta

All cells produce IFN beta + all tissues have IFNAR receptors

Question 7

What is IFN beta induction triggered by?

Answer 7

IRF-3

Question 8

Name a cell type that is specialised for producing IFN alpha. What do these cells express high levels of?

Answer 8

Plasmacytoid dendritic cells

IRF-7

Question 9

How many genes are there for IFN alpha and IFN beta?

Answer 9

Alpha: 13/14 isotypes
Beta: 1

Question 10

Which IFN comes under type II interferon?

Which cells produce this? Which receptor do these signal through?

Answer 10

IFN-gamma: specialist immune signalling molecule
Produced by activated T cells+ NK cells
IFNGR

Question 11

Which IFN falls under type III IFN? Which receptors do type III IFNs signal through?

Answer 11

IFN-lambda
L-28 receptors
IL-10 beta receptors

Question 12

Where are L-28 and IL-10 beta receptors mainly present?

Answer 12

Epithelial surfaces

E.g. respiratory epithelium

Question 13

Which organ is IFN lambda very important in?

Answer 13

Liver

Question 14

How does the innate immune system recognise non-self?

Answer 14

PRRs (pattern recognition receptors) on innate immune cells recognise PAMPs (pathogen-associated molecular patterns)
Often sense nucleic acids

Question 15

Name two receptors that are involved in detecting the presence of viruses and state where they are found.

Answer 15

RIG-I like receptor (RLRs): cytoplasmic

Toll-like receptors (TLRs): plasma membrane + endosomal membrane, mainly found in Plasmacytoid dendritic cells

Question 16

Describe RIG-I signalling.

Answer 16

RIG-I like receptors recognise ssRNA in the cytoplasm + signal through MAVS (mitochondrial)
Signals downstream, leading to phosphorylation of IRF3 which then dimerises + acts as a TF for generation of IFN-beta

Question 17

Describe TLR signalling.

Answer 17

TLR detects nucleic acids in the endosome (not normal)
Signals to molecules outside the endosome (MyD88) + sends various TF’s to the nucleus
Results in switching on of expression of IFN alpha + beta

Question 18

Describe DNA sensing.

Answer 18

Mainly done by cGAS
= enzyme that binds to dsDNA in the cytoplasm + synthesises cGAMP (2nd messenger)
cGAMP binds to STING (found on endoplasmic reticulum)
Triggers phosphorylation of IRF3, IRF3 dimerises, enters nucleus as TF, promotes synthesis of IFN beta

Question 19

Describe the structure of IFN receptors for IFN alpha and IFN beta

Answer 19

Heterodimers of IFNAR 1 + IFNAR 2

Question 20

Describe the signalling from IFNAR receptors

Answer 20

Binding leads to signalling cascade involving JAK + STAT
Results in phosphorylation of STAT molecules
STAT molecules dimerise + enter nucleus
Bind to a promoter + regulates transcription of 100s of new genes

Question 21

What is IFITM3? What does lack of IFITM3 result in?

Answer 21

Sits on membrane of endosomes
Prevent fusion of virus membrane with endosomal membrane so virus gets trapped in the endosome
Lacking IFITM3 results in more severe influenza

Question 22

What are Mx1 and Mx2?

Answer 22

Mx can form multimers that wrap around nucleocapsids of incoming viruses: nullifies the viral genomes
Mx1: inhibits influenza
Mx2: inhibits HIV

Question 23

Describe the actions of Protein Kinase R. When is PKR activated by cells?

Answer 23

Prevents ribosomes from binding to mRNA so NO NEW genes will be TRANSLATED
An extreme measure + a last resort – only activated when the cell has no other option

Question 24

Name a family of genes that suppress the cytokine signalling and turn off the response.

Answer 24

SOCS

Question 25

State 6 mechanisms of viral evasion of the IFN response.

Answer 25

``` Avoid detection by hiding the PAMP Interfere globally with host cell gene expression +/or protein synthesis Block IFN induction cascades Inhibit IFN signalling Activate SOCS Replication strategy insensitive to IFN ```

Question 26

Explain how hepatitis C controls the interferon response.

Answer 26

NS3/4 protease cleaves MAVS MAVS is important in detecting Hep C through the RIG-I pathway Thus Hep C is not detected

Question 27

Explain how influenza controls the interferon response.

Answer 27

NS1 protein Acts an antagonist to IFN induction by binding to the RIG-I complex + preventing activation of the signalling pathway Also prevents nuclear processing of newly induced genes

Question 28

What type of virus are Pox and Herpes viruses? What does this allow them to encode?

Answer 28

Large DNA viruses | Encode accessory genes to evade immune responses

Question 29

What do Pox viruses encode that helps deal with the interferon response?

Answer 29

Encode soluble cytokine receptors that mop up IFN + prevent it from reaching its receptors

Question 30

Describe a potential therapeutic use of the soluble cytokine receptors encoded by Pox viruses

Answer 30

Could be useful in AI or inflammatory conditions where IFN + other cytokines are produced in abundance

Question 31

What can result from viruses interfering with the immune response?

Answer 31

Skewing of immune response resulting in immunopathology

Question 32

Describe how viral infections can cause cytokine storm.

Answer 32

Lots of virus propagation, induces high IFN production | accompanied by massive release of TNF alpha + other cytokines

Question 33

What is a serious consequence of cytokine storm?

Answer 33

Pulmonary fibrosis – due to accumulation of immune cells in the lungs

Question 34

Explain why viruses that can't control interferon can be used as the next generation of live attenuated vaccines.

Answer 34

They're able to infect cells + will replicate sufficiently to be able to mount an immune response but won't replicate to the extent where it causes disease

Question 35

Viruses that can't control interferon can't be propagated in normal healthy cells. What is the solution to this issue?

Answer 35

Propagate in cells deficient in IFN response

Question 36

Explain why interferons are not frequently used as an antiviral therapy.

Answer 36

Stimulate production of several cytokines which cause unpleasant side effects

Question 37

What disease has IFN been used to treat?

Answer 37

Hepatitis C

Question 38

Explain the reasoning behind using IFN-lambda as a treatment for influenza.

Answer 38

Receptors for IFN lambda are only found on epithelial surfaces (site of infection of influenza) IFN lambda can't signal through immune cells + cause immunopathology Only induces an antiviral state in epithelial cells

Question 39

Explain how oncolytic viruses would work.

Answer 39

Viruses engineered to uniquely replicate in tumour cells + kill them Cancer cells are unable to mount a proper IFN response So, a virus unable to control the IFN response will NOT be able to replicate in healthy cells but will be able to infect + replicate in cancer cells

Question 40

What can lead to increased susceptibility to herpes simplex virus, thus resulting in encephalitis?

Answer 40

Inborn errors of certain genes result in lack of CNS intrinsic interferon response

Question 41

Give 2 examples of viruses that can trigger a cytokine storm

Answer 41

Dengue haemorrhage fever | Sever influenza