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2: Interferons Flashcards

1
Q

Type 1 interferons

A

Polypeptides secreted from infected cells

Type 1 = IFN alpha & beta
IFN-beta can be secreted by ALL cells and only has one type
IFN-alpha has multiple isotypes
Plasmacytoid dendritic cells are specialised in secreting IFN-alpha

Works via IFNAR receptors
Release is triggered by IRF (interferon releasing factor)

3 functions of interferons:

  1. Production of ISGs that induce antimicrobial state in infected cell + neighbouring cells
  2. Modulates INNATE response (promote antigen presentation + NK cells)
  3. Activates the ADAPTIVE immune response
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2
Q

Type 2 interferons

A

Type 2 = IFN gamma

Produced by activated T cells and NK cells
Signals through IFNGR receptor

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3
Q

Type 3 interferons

A

Type 3 = IFN lambda

Important at epithelial surfaces

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4
Q

What are types of immune response to virus

A

Intrinsic
Innate
Adaptive

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5
Q

Explain intrinsic immunity

A

ZAP can scan viral RNA for CpG
If it has too many CpG sequences, ZAP binds and targets it for RNA degradation
Virus can no longer replicate

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6
Q

How do we detect viruses? Give examples of receptors

A

PAMPS detected by PRRs

PRRs:
Rig-like receptors (RLRs)
Toll-like receptors (TLRs)
DNA sensors (cGas)

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7
Q

Differences between the PRRs

A

TLRs are membrane proteins (i.e. detect things from outside/inside)

RLRs are cytoplasmic (e.g. RigI)

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8
Q

Explain interferon induction with RLRs

A

RLR (e.g. RigI) detects abnormal nucleic acid in cytoplasm (e.g. ssRNA)
Conformational change in RigI and activates Mavs (on surface of mitochondria)
Mavs signals downstream proteins
Irf3/7 get phosphorylated then dimerise and enter nucleus
Bind to promoter sites on DNA
Induces transcription of IFN beta

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9
Q

Explain interferon induction with TLR

A

TLR3/7/8 detects foreign nucleic acid (RNA)
Downstream signals lead to phosphorylation of Irf3
Leads to gene expression of Type 1 IFNs

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10
Q

Explain interferon induction with cGAS

A 
DNA viruses (e.g. Herpes)
DNA in cytoplasm which shouldnt be there
cGAS detects DNA PAMPs
cGAS synthesises cGAMP
cGAMP binds to STING (membrane of RER)
STING phosphorylated -> IRF3 phosphorylated -> expression of Type 1 IFNs
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11
Q

What happens after IFN produced?

A

IFN-beta is soluble cytokine
Released out of cell
PARACRINE signalling to neighbouring cell
AUTOCRINE signalling to same cell where it was produced
Paracrine signalling -> neighbouring cells produce hundreds of ISGs (antiviral mediators), creating an anti-viral environment within cell

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12
Q

Examples of ISGs

A

Protein kinase R = inhibits translation

IFITM3 = restricts virus entry through endosomes (e.g. influenza)

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13
Q

Explain MX1/2

A

Form multimers that wrap around nucleocaspids of incoming viruses

MX1 inhibits influenza
MX2 inhibits HIV

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14
Q

How long does antiviral state last

A

Maintained for several hours only

After that the ability to respond to IFN is lost due to negative feedback

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15
Q

What turns off responsiveness to IFN

A

SOCS

Suppresses cytokine signalling

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16
Q

Ways in which viruses evade the IFN response?

A
  • Hide PAMPs
  • Interfere with host cell gene expression (so no IFN produced)
  • Block IFN cascade by destroying/binding
  • Inhibit IFN signalling
  • Block action of individual antiviral enzymes induced by IFNs
  • Activate SOCS
  • Replicate quickly before neighbouring cells respond to IFN
17
Q

Give 4 examples of ways viruses evade interferon detection.

A

Hep C: protease cleaves Mavs

Influenza: NS1 binds to Rig-I/RNA complex, prevents activation of signalling pathway. Also enters host nucleus and inhibits translation

Ebola: VP35 inhibits Rig-I, VP24 stop IFN signalling in neighbouring cells

Pox viruses: encode soluble cytokine receptor
Mops up cytokines and stops their action.
Can potentially be used for future immuno-regulatory drug, since it can mop up cytokines in immunopathological diseases like rheumatoid arthritis

18
Q

What are the consequences of viral infection?

A
  1. Virus infects and damages/kills host cells
  2. Innate immune response kills infected cells
  3. BUT bystander cells also killed by immune response
19
Q

Explain how viruses skew the immune response

A

Many viruses MODULATE the immune response which results in advertant pathology (i.e. we feel ill)
Interferons can be immunopathologic

20
Q

Explain cytokine storm

A

Virus replicates -> High IFNs -> Massive release of TNFa + other cytokines
Important: viruses are not being controlled by the IFNs so they replicate and induce more cells to release even more IFNs
Clinical outcome depends on vigour of innate immune system
This varies with age

Typical of Dengue feveer, severe influenza and Ebola

21
Q

What are the mediators of cytokine storm?

A

TNF
IFN alpha/beta/lambda
IL-1/6
CCL2

22
Q

Consequences of cytokine storm?

A 
Endothelial dysfunction (leaky)
Inflammatory response (sepsis syndrome)
Pulmonary fibrosis
23
Q

How can IFN-lambda be used for influenza therapy?

A

IFN-lambda only has receptors on EPITHELIAL cells
whereas IFN-alpha/beta have receptors on ALL cells (including immune cells, leading to immunopathology)

Treatment would induce anti-viral state only in epithelial cells. Hence doesn’t have the side-effects that IFN-alpha/beta would have

24
Q

Live-attenuated vaccines in the future?

A

Engineer viruses so that they cannot control IFN
High level of IFN produces rapid immune response

Cells that are deficient in the IFN response pathway (i.e. lack certain proteins like Rig-I) can be used to GROW these attenuated virus strains

25
Q

How is IFN affected in cancer cells?

A

Cancer cells are IFN deficient (they dont use the system)
Allows them to avoid apoptosis/immune response and grow uncontrollably

Because of this viruses can replicate very well inside tumours

Anti-cancer viruses that are deficient in counteracting the IFN system are being developed
This means they will be much more specific to cancer cells than normal cells
(Normal cells have IFN system but cancer cells don’t, so virus more likely to survive in cancer cell)

26
Q

What are 2 types of viruses with genetic drift for which we have vaccines for?

A

Influenza

Polio

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