Pathogen Recognition Receptors Flashcards
What kind of response does innate immune system have to bacteria
Inflammatory
What response does innate immune system have to Viruses
Interferon response
What fine tunes hose respond to pathogen
The signalling coming from Receptors
What are TLR homologous too
Drosophila Toll
What Resposne do TLR mainly induce
Pro-inflammatory response in innate immunity
What are he functional clusters of PAMPs and what is the basis for the clusters
Lipid
Protein
Nucleic acid
Based on what TLR binds too
Where are the TLR localised within cell
TLR1 , 2 , 6 and 4 are in cell membrane. Are lipid cluster
TLR 3, 7, 8, 9 in endosome
Membrane Are nucleic acid cluster
TLR 5,11,12are for flagellin
What mediates TLR inflammatory response
NF-Kb and MAPK
What is MyD88
A Toll/interleukin-1 receptor TIR
Essential. TIR and DD–containing adaptor protein
Facilitates formation of signalling complexes
Which TLR uses multiple adaptor proteins
TLR4 ending in NF-Kb signalling
And or IRF3 signalling
What TLR uses MyD88 independent pathway
What does it detect
What TIR adaptor protein does it use
TLR3
Detects dsRNA
Uses TRIF adaptor protein (or TICAM
TRIF platform for NF-Kb activation and IRF3 transcription factors
TLR3 is potent interferon activator
Name a gene defect that affects negative regulation
A20 gene defect stops negative regulation of inflammatory
Causes inflammatory diseases
What happens to TLR4?
Endocytsosed in endosome from cell membrane
Mutations can lead to lack of NF-Kb. What can this cause
Loss of inflammation and therefore reverent Bacterial infections
How have pathogens evolved to intervene with signalling?
Evolved to release inhibitory molecules to interfer with signalling and halt innate immune response
No/reduced cytokine/interferon response
Why are TLR good drug targets
Direct immune response so can be effective drug targets
TLRs can be effective adjuvants in vaccines to skew immune response in certain direction
Give an example of TLRs being used as adjuvant
PolylC in vaccines induce an anti viral response
What is IRAK-4 deficiency
What happens to those with it
Means no MyD88 dependent TLR signalling
Suffer disposition to Bacterial infection
High chance of death before 2
Likely to have invasive pneumococcal diseases
Likely to have staphylococcal disease
Where were dectin Receptors originally found
Dendritic cells
What is dectin 1
TLR independent receptor for fungi
C-lectin related to mannose receptor
Where is dectin-1 expressed
Expressed on immune cells (mainly phagocytes) at portals of pathogen entry
Neutrophils, monocytes and macrophages
What is dectin-1 main receptor for
Beta-glucans from zymosan(yeast particle)
Carbohydrate polymer found in cell wall of fungi and some bacteria
What do mutation in dectin genes cause
Infection and disease
Promoter mutations can affect expression levels of receptor
Leads to vulnerability to particular infection
E.g. Onychomycosis and vaginal candidiasis
Role of intracellular receptors ?
Work when bacterium has evaded cell defences and infected a cell
Structure of Nod1/nod2
TIR/CC—–NBD—-LRR
Caspase recruitment domain
Nucleotide binding domain
Leuxine rich repeat
What does Nod1/Nod2 recognise
Peptidoglycans from bacteria
Only recognised once they enter cell
Leads to NFkB activation and pro inflammatory cytokines
People with Nod2 knockout are?
More prone to oral listeria infections and salmonella as they replicate in cytoplasm
What do other NLR proteins recognise?
DAMPS
PAMPS
degrdative constituents of peptidoglycan (component of Bacterial cell wall)
What are degradation constituents of peptidoglycans
Nod2 ligand: muramyl dipeptide (MDP)
Nod1 ligand iE DAP (mostly gram -be bacteria)
NLR also found in plants and have similar domains
How does NOD signalling work
- Ligand binding induced NOD oligomerisation
- Conformational changes present CARD domains
- RIP2 kinase recruited and induces ubiquitylation
- RIP2 recruits TAB-TAK1 complex which can phosphorylase the IKK and MAP3K complexes
- Results in activation of NFkB and MAPK pathway
Triggering inflammation
What do defects in NOD genes lead too
Crohn’s disease due to defect in NOD2
Overstimulation of NFkB pathway leading to Overinflammation
Researchers not sure if due to too many bacteria or over detection of bacteria
I think could likely be both as trigger an effect that works together causing
Nucleic acid sensing within cells happens where and how?
Occurs in cytsol
Main sensors are RNA helicases
Detect RNA via helicase domain and transmit signals through amino terminal CARD domains
Induce NFkB and IRF signalling pathways
Found in all different types of cells
Signalling proteins tend to cluster around mitochondria
