interferons

Question 1

What is an interferon

Answer 1

Interferon (IFN) is a soluble cytokine secreted by infected cells, and a ‘master regulator’ of the immune response

Question 2

What are type I interferons

Answer 2

Polypeptides secreted from infected cells

IFN-alpha nd IFN-beta

Question 3

What are the functions of type I interferons

Answer 3

1. Induce antimicrobial state in infected and neighbouring cells
2. modulate innate response to promote Ag presentation and NK
3. Activate the adaptive immune response

Question 4

What cells secretes IFN-beta and what is induction triggered by

Answer 4

IFN b is secreted by all cells and IFNAR receptor is present on all tissues.
IFNb induction is triggered by IRF-3.

Question 5

What cells secretes IFN-alpha and what structure do they express

Answer 5

Plasmacytoid dendritic cells are specialised (though can be secreted by all cells)
They express high levels of IRF-7 constitutively

Question 6

Describe the genetics of type I interferons

Answer 6

One gene for IFN b
13/14 isotypes of IFNa
(IFN-b made first)

Question 7

What are type II interferons, what are the produced by and how does it signal

Answer 7

IFN-gamma
Produced by activated T cells and NK cells
Signals through its receptor IFNGR.

Question 8

What are type III interferons and how does it signal

Answer 8

IFN-lambda

Signals through receptors IL28R (+IL10b) that are mainly present on epithelial surfaces.

Question 9

What is the role of IFN-lambda

Answer 9

important at epithelial surface

Polymorphisms are associated with improved outcome from HCV and HBV

Question 10

Which pathogenic features are involved in differentiating self form non-self

Answer 10

Pathogen Associated Molecular Patterns, PAMPs

Question 11

Which receptors are involved differentiating self form non-selfin

Answer 11

Pattern Recognition Receptors, PRRs
Often sense foreign nucleic acid
Cytoplasmic RIG-I like receptors RLRs, endosomal Toll like receptors TLRs
Cytoplasmic nucleotide oligomerization domain receptors NLRs

Question 12

Explain how pathogenic nucleic acid can be sensed by different receptors

Answer 12

Sense of viral nucleic acid via TLRs, RLRs and DNA sensors

1. Interferon induction as RNA is sensed by RIG-I and/or mda-5
2. TLRs sense viral RNA, especially in dendritic cells, and signal through Myd88
3. DNA is sensed by cGAS that signals through STING

Question 13

Describe herpes simplex encephalitis (what it is the most common cause of, prevalence and who it infects)

Answer 13

most common cause of sporadic encephalitis in the Western world
Prevalence of 1/10,000.
Most common in childhood, affecting previously healthy individuals on primary infection with HSV-1.

Question 14

Explain the process of IFN induction

Answer 14

1. PAMP recognition at the cell surface signals IFNβ transcription
2. IFN then has auto- and paracrine effects via IFN-𝛼 receptor on all cells
3. signalling de novo transcription of interferon-stimulated genes (ISGs)

Question 15

Give examples of interferon stimulated genes

Answer 15

Protein kinase R (PKR) - inhibits translation + activated NFkappaB
2’5’OAS - prevents translation
Mx - inhibits incoming viral genomes (movement)
ADAR - induces errors during viral replication
Serpine - activates proteases
Viperin - inhibits viral budding

Question 16

How does IFITM3 restrict virus entry

Answer 16

Through endosomes

Stops fusion of the endosome membrane

Question 17

What does Mx1 and Mx2 inhibit

Answer 17

Mx1 inhibits influenza, Mx2 inhibits HIV

Question 18

Explain how Mx genes work

Answer 18

GTPase with homology to dynamin

Mx can form multimers which wrap around the nucleocapsids of incoming viruses.

Question 19

Explain how antiviral state self regulates to limit damage

Answer 19

IFN response may only be maintained for several hours
Subsequently the ability to response to IFN is lost due to negative regulation
SOCS suppressor of cytokine signalling genes turn off the response

Question 20

Give examples of how viruses evade the IFN response

Answer 20

Avoid detection by hiding the PAMP
Interfere globally with host cell gene expression and/or protein synthesis
Block IFN induction cascades by destroying or binding
Inhibit IFN signalling
Block the action of individual IFN induced antiviral enzymes
Activate SOCS
Replication strategy that is insensitive to IFN

Question 21

Give examples of viruses that can control interferon by stopping activation

Answer 21

Hep C

Influenza

Question 22

Explain how Hepatitis C controls interferon

Answer 22

NS3/4 protease acts as antagonist to interferon induction by cleaving MAVS.

Question 23

Explain how influenza controls interferon

Answer 23

NS1 protein acts as antagonist to interferon induction by binding to RIG-I /TRIM25/RNA complex and preventing activation of signalling pathway, and also prevents nuclear processing of newly induced genes.

Question 24

Explain how the sensor system is destroyed (?????????)

Answer 24

HCV protease NS3/4A cleaves MAVS

Question 25

How do pox viruses control interferon action

Answer 25

Pox viruses prevent the signal getting through

More than half the pox virus genome is comprised of accessory gees that modify immune response.

Question 26

Describe the overall damage caused by a virus

Answer 26

A combination of damage of infected cells by virus and damage of infected and bystander cells by the immune response

Question 27

What occurs in the cytokine storm and give examples of diseases that may cause it

Answer 27

Virus replicates, induces high IFN accompanied by massive TNFa and other cytokines.
The virus is resistant to the inhibitory effects of cytokines so replicates unchecked. Thus, it induces even more IFN and even more cytokines, resulting in immune pathology and potentially death.

typical of Dengue haemorrhagic fever, severe influenza infections and Ebola.

Question 28

Describe the use of IFN as an antiviral treatment

Answer 28

HCV, pegylated IFN often used with ribavirin

Associated with unpleasant side effects

Question 29

How can viruses that lack ability to control interferon be used as live attenuated vaccines

Answer 29

Viruses deficient in control of IFN are attenuated in IFN competent cells .
The high IFN levels they induce can also recruit useful immune cells, IFN acting as an ‘adjuvant’.

Cells naturally or engineered to be deficient in IFN response can be used to grow these attenuated virus strains.

Question 30

How do virus infection lead to inadvertent pathology

Answer 30

many viruses change the immune response to increase their own replication / transmission, and this can result in inadvertent pathology