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Rob's Microbiology MCD > Microbiology 2: Interferons > Flashcards

Microbiology 2: Interferons Flashcards

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1
Q

What do the case reports at the beginning relate to

A

Basically all of them have mutations in their interferon receptor so that they cannot detect when they are virally infected which they inherited from parents

This led to inability to control viruses which most people are fine with, even a vaccine in one case

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2
Q

What is often a manifestation of primary herpes simplex infection in a person with a genetic fault in their interferon pathway

A

Herpes Simplex Encephalitis

HSE is the most common cause of sporadic encephalitis in the Western world

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3
Q

Immune response to viruses

A

Intrinsic (physical barriers, mucus etc.)

Innate immunity

Acquired immunity

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4
Q

Give an example of intrinsic immunity against viruses

A

Intrinsic immunity

Basically just proteins within cells which bind to CpG (i.e. CG base sequence) which are overexpressed in virus RNA compared to ours.

If there are lots of CG repeats, ZAP binds and then recruits an RNA exosome to degrade the viral RNA

Viruses have adapted to downregulate their CG sequences to reduce detection by ZAP

Blunt system

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5
Q

What are interferons

A

TRANSFERABLE FACTORS produced by cells exposed to a virus

Binds to receptors on neighbouring cells

Then upregulates the synthesis of ISGs

This makes the interferon bound cell refractory to infection

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6
Q

What are ISGs

A

‘Interferon stimulated genes’.

Interferon binding (the interferon was released from a neighbouring cell exposed to virus, remember) upregulates the transcirption of these genes

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7
Q

How will you feel if given interferon

A

ILL because the ISGs produce proteins (chemokines and cytokines) which make you feel ill and lethargic and achey

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8
Q

What are type 1 interferons

A

Polypeptides secreted from infected cells

Type 1 interferon= IFNa and IFNb

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9
Q

What is the function of type 1 interferon

A
  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
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10
Q

Which cells are type 1 interferons produced by

A

Any cell, and any cell can respond to them

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11
Q

Outline how type 1 interferon production might occur

A

Virally infected cell.

Produces IFNb

Neighbouring cell (which is not yet infected) binds it, upregulating ISGs and enters an antiviral state

Dendritic cells might then produce IFNa which will help adaptive immune response

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12
Q

How many IFNa and IFNb genes

A

13 or 14 subtypes of IFNa, but only one IFNb

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13
Q

Which cells secrete and respond to IFNb. What triggers IFNb induction

A

IFN b is secreted by all cells and IFNAR receptor is present on all tissues. IFNb induction is triggered by IRF-3 (mentiond in a case report!).

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14
Q

Which cells secrete and respond to IFNa.

A

Plasmacytoid dendritic cells pdcs are specialist IFNa secreting cells.

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15
Q

Which molecule do pdcs express

A

They express high levels of IRF-7 constitutuvely.

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16
Q

What is type II interferon

A

IFNg, acts on different receptor (IFNGR) to type I (IFNAR)

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17
Q

Where is type II interferon produced

A

Produced by activated T cells and NK cells

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18
Q

What is type III interferon where does it act

A

IFN lamda, signals to epithelial cells on receptor IL28R and IL10b.

Doesn’t work on immune cells

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19
Q

Give examples of where IFNlamda is important

A

Resp tract and liver`

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20
Q

How is IFN lamda involved in HCV and HBV

A

Polymorphisms in IFN-lamda associated with improved outcome from HCV and HBV both spontaneous clearance and response to antiviral therapy

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21
Q

How do you differentiate self from nonself

A

PATHOGEN ASSOCIATED MOLECULE PATTERNS

detected with PRRs

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22
Q

Give examples of PRRs.

What do they often detect

A

PRRs often sense FOREIGN NUCLEI ACID

cytoplasmic RIG-I like receptors= RLRs,

endosomal Toll like receptors= TLRs

Cytoplasmic nucleotide oligomerization domain receptors = NLRs

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23
Q

Were are TLRs, RLRs and DNA sensors located

A

TLR- membrane or endosome

RLR- cytoplasm

DNA sensor- cytoplasm

24
Q

Give exampe of DNA sensor

A

cGAS

25
Q

How is interferon switched on by RIGI

A

RIGI recognises non-self RNA PAMPs

This induces conformational change in the RIGI

Interacts with MAVs (mitochondrial associated viral signaller)

MAVs signals through complexes which phosphorylates IRF 3 (in the case of most cells) or IRF 7 (for Plasmacytoid dendritic cells)

Causes dimerisation of 2X IRF which enters nucleus

Act as TFs (set down on promoter region) to upregulate the IFN gene (in the case of most cells this will be IFNb, and for the pdcs IFNa)

IFN produced and secreted

26
Q

How is interferon switched on by TLRs

A

Basically the same, apart from that TLRs are from around the membrane or in endosomes

TLRs activate TRIF and Myd88 slightly diffferent downstream signalling molecules but still ends up with IRF binding and IFN type 1 gene upregulation

27
Q

What do TLR, RLR detect, what about DNA sensor

A

The TLR and RLR detect viral RNA molecules

DNA sensor (cGAS) needed to detect viral DNA

28
Q

T/F having DNA in the cytoplasm is more wrong for cells than having viral RNA

A

TRUEEEEE

Because DNA should be in the nucleus,

whereas there is mRNA meant to be in the cytoplasm (although the human RNA in the cytoplasm should be capped, polyadenylated and associated with robosomes, whereas the virus RNA will not have this, making it susceptible to recognition by the PRR, such as RIGI and TLR)

29
Q

How is interferon produced by viral DNA PAMPs

A

The DNA PAMP is detected by cGAS

When cGAS binds DNA it is phosphorylatd

It undergoes conormational change so it binds STING (equivalent to MAVS for the RNA pathway) which then gets phosphorylated and causes phosphorylation and dimerisation of IRF 3 and production of type I IFN

30
Q

Where is STING found

A

BOUND TO rER (whereas MAVS is bound to the mitochondria for the RNA pathway, the STING is bound to rER).

31
Q

What happens to the IFNb produced from the first cell

A

It then can bind to receptors on its OWN cell to upregulate production of ISGs = AUTOCRINE

AND

Binds to receptors on NEIGHBOURING cells to upregulated ISGs= PARACRINE

i.e. this then causes a hostile environment for the virus when it completes its replication in that cell so it cannot infect neighboring cells now

Interferon induces transcription of 100s of antiviral mediators

32
Q

Outline how IFNb binds to receptors

A

Binds to IFNAR heterodimer and upregulates lots of ISGs via the Jak/stat pathway

33
Q

Give examples of ISGs

A

PKR –> translation inhibition

2’5’OAS: destroys ssRNA (using RNAase), e.g of ebola, or measles virus

Mx: inhibits viral genomes

ADAR: induces error in viral replication

Serpine activates proteases

Viperin: inhibits budding

34
Q

What is IFITM3 action

A

ISG… PREVENTS viruses e.g. influenza from escaping the endosome.

(people with IFITM3 polymorphism such as CC, get worse flu and are more likely to succumb to virus. Increase hospitilisation… common in Asia (44%!)

35
Q

How does Mx work

A

GTPase with homology to dynamin

Forms multimers which wrap around nucleocapsids of viruses e.g. in influenza and lacross virus

36
Q

What do Mx1 and Mx2 inhibit

A

Mx1 inhibits influenza, Mx2 inhibits HIV

so influenza is targeted by IFITM3 and also by Mx1

37
Q

T/f IFNs lead to antiviral state which persists for days

A

F… IFN response may only be maintained for several hours

38
Q

How is IFN acton reduced

A

Subsequently the ability to response to IFN is lost due to negative regulation

SOCS suppressor of cytokine signalling genes turn off the response.

39
Q

How can virus eade IFN

A

Avoid detection by hiding the PAMP which the PRR usually sees

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

40
Q

How does hepatitis C control interferon

A

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

41
Q

How does influenza control interferon

A

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

42
Q

What type of viruses are pox and herpes

A

Pox viruses and herpes viruses are large DNA viruses

43
Q

Outline possible immunotherapy from pox

A

Vaccinia is a receptor on virus which is a SOLUBLE CYTOKINE RECEPTOR, vaccinia vaccine B18

I.e they mop up the cytokines released by immune system to stop itself from beng affected by the cytokines

These can be used in rheumatoid arthritis patients for example to downregulate cytokines and chemokines causing inflammation

44
Q

Outline how ebola evades interferon system

A

An ebola protein VP35 interferes with RIGI signalling so reduced interferon production

Interferon that is produced is less effective because VP24 then blocks signalling when the IFN receptor binds so you dont get the production of ISGs

45
Q

What accounts for pathology of viruses

A
  1. A combination of damage of infected cells by virus and
  2. damage of infected and bystander cells by the immune response (consequence of innate immunity)

THERE CAN BE AN IMBALANCE WHICH CAN RESULT IN TOO MUCH CYTOKINE AND EVENTUALLY ORGAN DAMAGE

46
Q

Why might a virus skew the immune response

A

To increase own replication and transmission.

But can result in inadvertant pathology

e.g. if it has recently crossed over from an animal, the virus might not know how to control the human immune reponse (i.e. the human cannot control the viral load so you just keep getting more and more release of IFN and thus cytokines)

47
Q

What mechanisms do we have to prevent a cytokine storm

A

Different ISGs need different amounts of interferon to be switched on

Mx, which is just antiviral needs not very much, whereas IL6 which has many more systemic effects needs much more IFN to be switched on

48
Q

Outline the pathology of cytokine storm

A

Virus replicates, induces high IFN accompanied by massive TNFa and other cytokines.

49
Q

What are differences in outcome in a cytokine storm dependent on

A

reflect vigour of innate immune system, which may vary with age.

50
Q

Which diseases typically show cytokine storm

A

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

51
Q

Which mediators are involved in cytokine storm

A

ELEVATED:

TNFa, IFNa/b, IFNg, IL-1a/b, IL6 and CCL2

52
Q

What do the cytokine mediators produced ina cytokine storm result in

A

Endothelial dysfunction (increased permeability, altered barrier function)

Inflammatory responses (sepsis syndrome)

After –> fibrosis e.g. pulmonary fibrosis due to recruitment of fibrocytes and ECM deposition and T cell mediated immunopathology

53
Q

What can be a consequence of imbalance between virus and interferons

A
  1. Host range barriers (i.e. when a virus crosses from animal to human it can cause cytokine storm)
  2. Therapeutics
  3. Vaccines
  4. Oncolytic viruses
54
Q

Outline how IFN was used as treatment.

Why did it make you feel bad.

A

Used to be used for HCV (peyglated IGN)

Associated with unpleasant side effects because of the cytokines released when IFN binds to IFNAR on immune cells which induces flu feeling (i.e. the JAK/STAT pathway upregulates ISGs but also causes immunopathology by upergulating cytokines)

55
Q

What is a possible new treatment invoving IFN

A

IFN lamda

Acts on IL28R and IL10b which are mainly present on epithelial surfaces

So you get antiviral state in the immune cells but not the cytokine release from immune cells

56
Q

Outline IFN use in vaccine

A

Viruses that lack ability to control interferon as a new generation of live attenuated vaccines

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

The cells cannot control the IFN, so are easily destroyed by healthy immune system.The high IFN levels they induce can also recruit useful immune cells, IFN acting as an ‘adjuvant’.

57
Q

How could the IFN system be exploited in cancer treatment

A

IFN system used to detect incorrect DNA that occurs in cancer cells (as well as the incorrect DNA from viruses) and remember that the IFN response eventually leads to cell death…

so they are often downregulated in cancer cells (to let the cancer cells evade this sensor)

Therefore we can introduce into patients viruses which kill cells, and they will grow better in the cancer cells (in the normal cells the IFN will control the virus, but cancer cells this IFN is downregulated)

You engineer viruses than have low ability to combat the cell’s IFN response. They will still surivive in the cancer cells (because cancer cell has such low IFN) but will be killed in normal cells

Rob's Microbiology MCD (6 decks)

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