MM4 Innate immunity Flashcards
What falls under intrinsic immunity?
Complement
APOBEC3G
TRIM5 alpha
What is innate immunity?
The induced cell mediated response to infection. The main function of innate immunity is to prime the acquired immune response
How does APOBEC3G work?
It works by causing deamination of C–>U on the -ssDNA during reverse transcription of +ssRNA
Causes G–>A hypermutation on the +ssDNA strand
Destroys the coding and replicative capacity of the virus
Counter defence of HIV to APOBEC3G?
Vif
Viral infectivity factor
Targets the APOBEC3G for degradation
How does TRIM5 alpha function?
It functions by recognising viral retroviral capsids and preventing uncoating and reverse transcription
Why can human TRIM5 alpha not protect against HIV?
Thought that human TRIM5 alpha evolved in response to a PtERV infection 4 million years ago. The human TRIM5 alpha developed mutations to better prevent against PtERV infection. This has now made humans susceptible to HIV infection- cannot be a master of all.
What cell surface receptor TLRs are there?
TLR 2,4,5,6
What does TLR2 recognise?
Gram positive bacteria
Lipoprotein
Lipomannan LM
Lipoarabinomannan LAM
What does TLR5 recognise?
Bacterial flagellin
What does TRL4 recognise?
Gram negative bacteria
What cytoplasmic receptors must you know?
TLR 3,7,8,9
RIG-I like receptors:
RIG-I and MDA-5
What does TLR3 recognise?
dsRNA
What do TLR7 and TLR8 recognise?
ssRNA
What does TLR9 recognise?
CpG motifs
This is where a cytosine nucleotide is directly followed by a guanine nucleotide
5’-C-phosphate-G-3’
Unmethylated CpG motifs are not common in vertebrates and are indicative of viral infection
What doe RIG-I recognise?
Short dsRNA with 5’ triphosphate caps
What does MDA-5 recognise?
Long dsRNA
How do RLRs signal?
Via the Cardif/MAVs adaptors
Then leads to NFkB and IRF-3 production
All TLRs apart from TLR3 signal via which adaptor?
Myd88
TLR3 signals via?
TRIF adaptor
In the Myd88 independent pathway
TLR4 is capable of what signalling?
Both Myd88 dependent and independent signalling
IRF-3 leads to production of which interferon?
IFN-b
IRF-7 leads to the production of which interferon?
IFN-a
What is NF-kB?
It is a complex which is able to enter the nucleus and initiate transcription of many genes. It often leads to the production of pro-inflammatory cytokines
What prevents NF-kB entering the nucleus?
IkB
What needs to happen to IkB to allow NF-kB activation?
Phosphorylation and degradation of IkB
What are interferons?
The first cytokines identified
Proteins
Signalling molecules
Type I interferons are produced by?
Fibroblast cells
Type I interferons bind to which receptors?
IFNAR
Type I interferons include?
IFN-a
IFN-b
Type I interferons cause what?
- Antiviral state to be induced in neighbouring cells
- Up-regulation of MHC-I on cells
- NK cell activation
How many types of IFN-a and IFN-b?
14 IFN-a
1 IFN-b
Type II interferons bind to which receptors?
IFNGR
Type II interferons include?
IFN-g
Type II interferons are produced by?
Th1 T cells
NK cells
What do type II interferons do?
Lead to classical macrophage activation
Increased lysosomal activity of macrophages
Up-regulates their microbicidal activity
Causes macrophages to produce reactive oxygen and nitrogen species.
Oxygen is needed for ROS
L-arginine is needed for RNS
How is L-arginine transformed into nitric oxide?
Via iNOS
Inducible nitric oxid synthase
Which interferon is primarily produced before the amplification response?
IFN-b
Which interferon is primarily produced after the amplification response?
IFN-a
Describe interferon amplification?
IFN-b binds to IFNAR JAK-STAT signalling TYK-2 and JAK-1 phosphorylate STAT-1 and STAT-2 They form a complex with IRF-9 Complex is known as ISGF3 This enters the nucleus and binds to the ISRE ISG is activated IRF-7 --> IFN-a IRF-3 --> IFN-b
What leads to phosphorylated STAT-1 and STAT-2?
TYK-2 and JAK-1 Janus kinases
What is the ISGF3?
Interferon Stimulated Gene Factor 3
What is the ISGF3 composed of?
STAT-1
STAT-2
IRF-9
ISGF binds to ISRE which is?
Interferon Stimulated Response Element which is found within the promoter regions of ISGs= Interferon Stimulated Genes
ISG encoded products include?
Tetherin TRIM5 alpha APOBEC3G OAS= 2'-5' Oligoadenylate synthetase PKR IFITM1/2/3
What does tetherin do?
Binds retroviruses to prevent them escaping the cell and infecting new cells
What is OAS?
2’-5’- Oligoadenylate synthetase
What is PKR?
Protein Kinase R
IFITM3?
Present in the late endosome and can prevent fusion of influenza viruses
How does OAS work?
Recognises dsRNA
Leads to RNaseL production
All cellular RNA is degraded including host
OAS and PKR are both?
Interferon induced
PKR is induced by?
Interferon
PKR recognises?
dsRNA
How does PKR work?
Recognises dsRNA Autophosphorylation into active PKR Can phosphorylate eIF2-a Prevents it from working Translation is halted Also leads to NF-kB activation
How is cytosolic DNA recognised by?
cGAS
What is cGAS?
Cyclic GMP-AMP synthase
cGAS recognition of cytosolic DNA leads to?
GTP–> GMP
ATP –> AMP
cGAMP production: cyclic GMP-AMP
cGAMP leads to?
STING activation
STING leads to?
TBK1 recruitment
What does TBK1 do?
Phosphorylates and activates IRF-3
