Innate Immunity Flashcards
What is intrinsic innate immunity?
Includes APOBEC3G and TRIM5-alpha
Includes proteins that are constitutively expressed and can help to protect the body from infection
They are able to respond immediately
As the response is not induced they cannot tailor their response
Also includes complement- pre-formed pathway
Intrinsic innate immunity is particularly important in protecting against?
Retroviral infection
What is induced innate immunity?
This is the response that is pathogen induced. The type of PAMPs recognised by PRRs elicits an innate immune response. It is cell-mediated and includes antigen presenting cells such as macrophages and dendritic cells. Also includes phagocytic cells such as neutrophils
APOBEC3G and TRIM5-alpha are?
Intrinsic immune proteins
What is the function of APOBEC3G?
It is a constitutively expressed cellular protein
It becomes incorporated into the retrovirus virion
When the virus infects a new cell the APOBEC3G protein can cause hypermutation through deamination of C–>U on the minus strand of DNA during reverse transcription. results in G–>A mutation on the plus strand of DNA. This hypermutation prevents the retrovirus from integration and replication .
APOBEC3G interferes with?
Reverse transcription
What is the retroviral counter defence to APOBEC3G?
Vif
What is Vif?
Viral infectivity factor
What does Vif doo?
It targets APOBEC3G for degradation
TRIM-5 alpha does what?
Prevents viral uncoating and reverse transcription of retroviruses
Is human TRIM-5 alpha effective against HIV?
No
What is the theory for why human TRIM-5 alpha is ineffective against HIV?
The idea is that human TRIM-5 alpha acquired mutations and evolved to fight PtERV infection. However, as a consequence of these changes we are now more susceptible to HIV infection.
What are some membrane PRRs?
TLRs: 1,2,4,5,6
What are some cytoplasmic PRRs?
RLRs: MDA-5 and RIG-I
TLRs: 3,7,8,9
What are RLRs?
Rig like receptors
What are the two RLRs you must know?
MDA-5 and RIG-I
What does MDA-5 recognise?
It recognises long dsRNA
What does RIG-I recognise?
Short dsRNA with a 5’ triphosphate CAP
RIG-I and MDA-5 signalling?
Upon recognition of dsRNA they bind to signalling adaptor MAVS
This leads to IRF-3 and NF-kB production
Another name for MAVS?
Cardif
What are the cytoplasmic TLRs?
3,7,8,9
What does TLR3 recognise?
dsRNA
What do TLRs 7 and 8 recognise?
ssRNA
What does TLR 9 recognise?
Unmethylated CpG motifs
What are CpG motifs?
When a cytosine is followed by a guanosine in the 5’-3’ direction. TLR9 recognises unmethylated CpG motifs.
All TLRs except for TLR3 are capable of signalling via which adaptor?
Myd88 dependent pathway
TLR4 and TLR3 are capable of the Myd88 independent pathway which involves which adaptor?
TRIF adaptor
Signalling via Myd88 activates?
NF-kB
How does signalling via Myd88 work?
Recognition of the PAMP
Recruitment of Myd88
Recruitment of kinases
Kinases phosphorylate IkB
NF-kB is released and can enter the nucleus
Activates the expression of genes e.g. production of pro-inflammatory molecules
What is NF-kB?
It is a protein complex which can enter the nucleus and regulate the transcription of multiple genes
What is IkB?
Found bound to NF-kB. It inhibits NF-kB
How is IkB released from NF-kB?
Through phosphorylation of IkB by kinases
TLR3 signalling?
Myd88 independent
TRIF adaptor
Activation of IRF-3 and NF-kB
First cytokine discovered?
Interferons
What are interferons?
Signalling proteins
Cytokines
What are the type I interferons?
Alpha and beta
Type I interferons are produced by which cells?
Fibroblast
Type I interferon function?
- Activate NK cells
- Upregulate MHC-I expression
- Induce an antiviral state in cells
What receptor do type I interferons bind?
IFNAR
What is the type II interferon?
IFN-g
What cells produce IFN-g?
Th1 cells
NK cells
Action of IFN-g?
Activates macrophages- classical activation
Increases their microbicidal activity
Causes them to increase expression of reactive oxygen and nitrogen intermediates
IFN-g binds to which receptor?
IFNGR
Which type I interferon is produced first?
IFN-b
IFN-a is primarily produced after?
The amplification resposne
Which IRF leads to the production of IFN-a?
IRF-7
Which IRF leads to the production of IFN-b?
IRF-3
Describe the process of interferon amplification?
- Cell recognises PAMPs via PRRs
- NF-kB and IRF-3 are produced
- IFN-beta is produced and released
- IFN-beta binds to the IFNAR
- JAK-STAT signalling
- ISGF3 complex binds to the ISRE and activates ISGs
- Production of ISG encoded effectors and IRF-7
- IRF-7 leads to the production of IFN-a
What are the Janus kinases involved?
JAK-1
TYK-2
Describe JAK-STAT signalling?
- Binding of interferon to the receptor
- Recruitment of STAT-1 and STAT-2
- Phosphorylation of STAT-1 and STAT-2
- IRF-9 recruited
- STAT-1, STAT-2 and IRF-9 form an ISGF3 complex which can enter the nucleus
STAT-1, STAT-2 and IRF-9 form which complex?
ISGF3
What is ISRE?
Interferon stimulated response element
Where is ISRE located?
Within the promoter of ISG
ISG?
Interferon stimulated gene
ISG encodes which ISG effectors, some examples?
Tetherin TRIM-5 alpha APOBEC3G Intimin 1/2/3 PKR OAS
IRF-3 leads to the production of?
IFN-b
IRF-7 leads to the production of?
IFN-a
PRRs do not only recongise PAMPs, they are also able to recognise DAMPs which are?
Danger associated molecular patterns
Examples of a DAMP?
Cytosolic DNA
What is cytosolic DNA recognised by?
cGAS
What is cGAS?
Cyclic GMP-AMP synthase
When cGAS recognises the cytosolic DNA?
cGAS is activated and causes GTP and ATP to become cyclic GMP-AMP (cGAMP)
cGAMP binds and activates STING
STING leads to TBK1 kinase which leads to IRF-3 activation/phosphorylation
Leads to IFN-b production (production of type I IFN response)
IFITM3 ISG has a role in?
Preventing influenza from fusing and leaving late endosomes
IFITM1/2/3 have a role in?
Preventing viral entry
Role of tetherin?
Prevents retroviruses from infecting new cells, binds retroviruses that bud off
OAS stands for?
2’-5’ oligoadenylate synthetase
What activates OAS?
dsRNA
When dsRNA binds to OAS?
Causes activation of RNaseL
What does RNaseL do?
Degrades all intracelluar RNA, pathogen and cellular alike
Prevents protein synthesis
What is PKR?
Protein Kinase R
PKR is activated by?
dsRNA
Once PKR binds dsRNA?
Autophosphorylation
Can then phosphorylate eIF2 which is needed for initiation of translation
Prevents translation from occurring
PKR also leads to?
NF-kB activation
