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Infection and Immunity > Innate immunity against viruses and viral evasion strategies > Flashcards

Innate immunity against viruses and viral evasion strategies Flashcards

1
Q

What are the components to innate antiviral immunity?

A

Barriers at sites of microbe entry
Intrinsic defences
Phagocytosis
Complement
Inflammatory response
Cytokines and interferon
NK cells

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2
Q

What are the sites of microbe entry?

A

Conjuctiva
Respiratory tract
Alimentary tract
Urogenital tract
Anus
Skin
Arthropod
Capillary
Scratch/injury

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3
Q

What are the physical barriers?

A

Skin
Mucosal surfaces

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4
Q

What are the chemical barriers?

A

pH
Secreted factors

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5
Q

What are sentinel cells?

A

Any cell that has a prominent role in host defence
e.g. macrophages, DCs

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6
Q

What are the intrinsic defences?

A

Apoptosis
Restriction facotrs/intrinsic immunity
Epigenetic silencing
RNA silencing
Autophagy/Xenophagy

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7
Q

Why is apoptosis bad for the virus?

A

It prevents completion of the life cycle and triggers surface signals for clearance by macrophages

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8
Q

How does adenovirus evade apoptosis?

A

E1B-19K protein expressed by adenovirus counteracts E1A-induced intrinsic apoptosis
It is a viral BCL-2 homologue
Prevents oligomerisation of BAX and BAD, preventing mitochondrial pore formation and no cytochrome c, Smac release
XIAP will therefore inhibit apoptosis by binding to effector caspases

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9
Q

How does Kaposi’s sarcoma-associated herpesvirus (HHV-8) evade apoptosis?

A

Viral Bcl-2 homologue inhibits mitochondrial pore formation by binding BAK
vFLIP protein blocks interaction of death receptor-adaptor complex with cellular effector FLICE (procaspase-8), which prevents initiation of caspase cascade
vIAP protein binds to apoptosome and prevents activation of effector caspases

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10
Q

What are restriction factors?

A

Host cellular proteins that act as a frontline defence against viral infections
They recognise and interfere with stages of the replication cycle of viruses and therefore block infection

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11
Q

Name some restriction factors

A

APOBEC3G
TRIM5a
Tetherin
SAMHD1

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12
Q

Describe APOBEC3G

A

A highly potent ssDNA cytidine deaminase
Associates with nascent HIV nucelocapsids and is incorporated into new virions
When these virions infect other cells and the viral transcription complex is formed, APOBEC3G deaminates cytidine to uridine, forming hypermutated defective proviruses or are degraded so cannot cause infection

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13
Q

Describe TRIM5a

A

Targets incoming capsids to proteasomes
Very species-specific
Block retroviral infections by binding viral capsids and preventing reverse transcription
Prevent uncoating of virus

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14
Q

How does tetherin work?

A

Blocks budding by enveloped viruses

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15
Q

Describe SAMHD1

A

A phosphohydrolase that converts dNTPs to inorganic phosphate and depletes the pool of dNTPs available to reverse transcriptase

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16
Q

How does HIV evade restriction factors?

A

Vpu protein removes tetherin from the cell surface
Vif impairs translation and intacellular stability of APOBEC3G
Vpx protein counteracts SAMHD1 to allow reverse transcription

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17
Q

What is epigenetic silencing?

A

A nuclear event where foreign DNA molecules that enter the cell are quickly organised into transcriptionally silent chromatin
Involves PML bodies
Silences DNA viruses e.g. adenoviruses and herpesviruses

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18
Q

What do large DNA viruses encode?

A

Proteins that prevent deposition of inhibitory histones and other chromatin compounds onto viral DNA

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19
Q

Describe phagocytosis as a component of innate viral immunity

A

Carried out in vertebrates by DCs, macrophages and neutrophils
Clears pathogens but also presents peptides on MHCs - this promotes development of reactivation of the adaptive immune system

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20
Q

How do phagocytes see viruses?

A

Macrophages have phagocytic receptors that bind microbes and their components
e.g. mannose receptor, complement receptor, lipid receptor, dectin-1, scavenger receptor

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21
Q

How does complement bind to some viruses in an antibody-dependent manner?

A

Classical pathway via direct binding of C1q to the envelope glycoproteins of some viruses
Lectin pathway via binding of MBL to viral surface carbohydrates
Alternative pathway on enveloped viruses

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22
Q

How do viruses evade complement?

A

Complement control proteins incorporated into envelope
Can be passive or active

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23
Q

Give examples of active evasion of complement

A

Vaccinia C3L gene product VCP is a complement control protein that binds to and inactivates C3b and C4b
Vaccinia B5R product recruits host complement control proteins into the envelope
KSHV-encoded KCP is incorporated into the virion and enhances the decay of classical C3 convertase and induces the degradation of activated complement factors C4b and C3b by a serine proteinase factor I

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24
Q

What is pinocytosis?

A

Cell ‘drinking’ - ingestion of liquid into a cell by budding of small vesicles from the cell membrane
Anything taken up by cells in pinocytosis is cleared by proteolysis and presented on the surface through MHC

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25
Why does pinocytosis occur?
For immune cells such as DCs, macrophages and neutrophils to sample their environment
26
What are the 2 distinct roles of macrophages in innate immunity?
Phagocytosis - material is destroyed in lysosomes Activated macrophages produce cytokines and chemokines to stimulate both innate and adaptive immune responses - triggers the inflammatory response and can promote local anti-viral state
27
What is the inflammatory response?
A generic defence mechanism whose purpose is to localise and eliminate injurious agents and to remove damaged tissue components
28
What does the inflammatory response lead to?
Enhanced permeability and extravasation Neutrophil recruitment Enhanced cell adhesion Enhanced clotting
29
What 2 signals are needed for activation of the inflammatory response?
Stimulation of transcription of pro-inflammatory cytokines and chemokines Activation of ICE/caspase-1 which cleaves the inactive precursor forms of IL-1B and IL-18 (the inflammasome)
30
What activated the inflammasome?
Viral PAMPs sensed by PRRs
31
Name some anti-viral PRRs
TLR3, 7, 8 and 9 RIG-I MDA5 DAI RNApol-III Ku70/80 AIM2 IFI-16
32
Where are TLR7, 8 and 9 expressed?
In plasmacytoid DCs and macrophages
33
Where is TLR3 expressed?
Expressed widely but shows elevated levels on myeloid DCs, macrophages, endothelial and epithelial cells
34
Where are RIG-I and MDA5 expressed?
Ubiquitous
35
Where are DAI, RNApol-III and Ku70/80 expressed?
Ubiquitous
36
Where is AIM2 expressed?
In macrophages
37
Where is IFI-16 expressed?
In macrophages
38
Why is an overactive inflammatory response bad for resolving influenza infections?
High pathogenicity strains can trigger cytokine storms that lead to severe lung damage
39
How is an overactive inflammatory response treated?
IL-1 antagonists and other anti-inflammatory drugs
40
How is inflammation evaded by viruses?
General block to inflammatory cytokine production Direct inhibition of caspase-1 Synthesis of scavenger receptors Blocking of inflammasome assembly NS1 inhibits RIG-I inflammasome
41
What do viruses trigger?
Production of anti-viral cytokines
42
What induces interferons?
Viral infection
43
What do interferons offer?
Cross-protection
44
What are the types of interferon?
Alpha Beta Epsilon Kappa Lambda-1, 2 and 3 Gamma
45
What do the IFN lambdas do?
Protect epithelial surfaces
46
What do IFN alpha and beta do?
Protect all other tissues
47
What is the antiviral state?
The result of a signalling pathway induced by IFN-a or IFN-b following viral infection Limits replication in infected cells and viral spreading in non-infected cells by
48
Describe IFN and the antiviral state
IFN-a/b binds to receptor and triggers signal transduction pathway (JAK/STAT pathway) This turns on 1500 genes
49
What does it mean when a virus cannot block the IF system?
It is severely attenuated
50
Give examples of severely attenuated viruses
Influenza NS1 stains are severely attenuated and can be used as the basis of vaccine strains BVDV Npro strain is severely attenuated and can be used as a vaccine strain PIV5VC is severely attenuated and can be used as an experimental vaccine
51
How is the IFB-b promoter activated?
Virus PAMPs bind PRRs Activates transcription factors NF-kB and IRF-3 in the nucleus IRF-3 activates PRD I/III on IFN-b promoter NF-kB activates PRD II on IFN-b promoter
52
What viruses inhibit activation of IFN-b promoter?
Paramyxovirus V and Influenza NS1 block PRRs, preventing recognition of PAMPs so no activation of NF-kB and IRF-3 BVDV Npro inhibits IRF-3 so no activation of PRD I/III
53
Describe how type 1 interferons signal
Through heterodimeric transmembrane receptor comprising subunits IFNAR1 and IFNAR2 Engagement of type 1 IFNs with the receptor causes dimerisation of the 2 subunits and autophosphorylation of JAK1 and Tyk2 These phosphorylate the intracellular domains of the receptors to establish docking sites for STAT1 and STAT2 STAT1 and 2 are subsequently phosphorylated by the JAKs Phosphorylated STAT1 and STAT2 form a heterodimer that binds IFN regulatory factor IRF9 in the cytoplasm, forming heterotrimeric transcriptional factor complex IFN-stimulated gene factor 3 (ISGF3) ISGF3 translocated to the nucleus and binds cis element IFN-stimulated response element (ISRE) This drives the transcription of hundreds of ISGs that are involved in the antiviral state
54
How do poxviruses inhibit the JAK/STAT pathway?
Produce secreted IFN-receptor-like decoy factors for IFNs to bind to instead of the actual heterodimeric transmembrane receptor
55
How does herpes simplex virus 1 inhibit JAK STAT?
Induces secretion of an IFN type 1 antagonising protein
56
How does measles virus suppress JAK STAT?
Suppresses IFN-a induced viral state but not IFN-g induced signalling Measles virus accessory proteins C and V form a complex with the IFNAR1 chain
57
How do influenza A viruses disrupt the JAK STAT pathway?
By reducing expression of the IFN receptor NS1 protein produced by influenza A viruses reduced IFN production and inhibits IFN signalling NS1 targets both chains of the IFNAR receptor by reducing their expression at the transcriptional level
58
How does EBV affect IFN signalling?
Encodes the protein BZLF1 that decreases ability of IFN-g to activate several genes in the pathway Inhibits phosphorylation of STAT1 Decreases expression of IFN-g receptor
59
Why are NK cells important in DNA virus infections?
NK cells secrete IFN-g to act against viruses and allow lysis of virally infected cells
60
How does CMV inhibit NK cell function?
Produces UL40 and UL142 proteins that act as decoy NK cell receptors Produces UL16 proteins that downregulate NK activating receptors

Infection and Immunity (33 decks)

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