3: Pathogen Recognition 🏁 Flashcards
Cellular components (5) and barriers (3) of the innate immune system and main function/s
Barrier
- Epithelial barrier: prevent entry
- Defensins: microbial killing
- Intraepithelial lymphocytes: microbial killing
Cells
- Neutrophils: early phagocytosis and killing
- Macrophages: efficient phagocytosis and killing, secretion of cytokines that stimulate inflammation
- NK cells: lysis of infected cells, activation of macrophages
- Mast cell: Release of granules
- Dendritic cell: Mediator for adaptive immunity: AG presentation
Name 3 problems and how pathogen recognition receptors overcome it
Enormous variability of microorganisms
- PAMPs are structures shared by large group of microbes
High mutation rate of microorganisms (e.g. Influenza)
- PAMPs must be constrained from mutational variation by being essential to microbial survival and pathogenicity
PAMPs need to be discriminated from non infectious self
- PAMPs are completely distinct from host structural patterns
Name 2 distinct ways of how PAMPs or DAMPs are recognized
Opsonins
Soluable factors that recognize conserved molecular patterns of bacteria, viruses or cells
PRRs
Pathogen recognition receptors on immune cells
List 4 important statements that fit to Opsonins / receptors of innate immune system
- only few number with broad specificity
- germ line-encoded, no rearranging
- PRR/Opsonin selection reflects coevolutionary process
- not a single physiological system (diverse mechanisms)
Name 4 different types of soluable pattern recognition receptors, their structure + function
Ficolins
fibrinogen-like domain that binds pathogen + collagen-like domain that binds complement system parts
Collectin like Mannan-binding lectin (MBL)
carbohydrate recognition domain + collagen-like domain that binds complement system parts
Pentraxin
long and short forms (e.g. acute phase proteins CRP and Amyloid) that bind ligands (Ca2+ dependent) to activate classical pathway of complement system
Galectins
binding of pathogen via carbohydrate recognition domain for cell-cell or cell-pathogen adhesion or transmebrane signalling
Which gene casette controls antifungal immune response in Drosophila and how ?
Is there a similar mechanism in humans (which factors)?
Gene cassette
Spätzle/Toll/Cactus controls the response: Protein Spätzle is being processing after antifungal response, binds to Toll receptor that inhibits antiinflammatory proteins Cactus/Dorsal
similar mechanism in humans
Spätzle: IL-1b
Toll: IL-1 receptor
Cactus/Dorsal: NF-kappaB, I-kappaB
Different pathogens and toll like receptors
- gram-
- gram+
- bacteria in general
- fungii
- foreign RNA
Where are toll like receptors expressed?
Gram-
- TLR4: LPS
Gram+
- TLR2: intercats with TLR1 and TLR6 and binds lipids (Lipoproteins)
Bacteria in general
- TLR5: flagellins
- TLR9: bacterial genomic DNA (presense of unmethylated CpG dinucleotides in contrast to methylated CpGs in mammalian genomes)
Fungii
TLR2 and 4: cell wall components like chitin, ß-glycan, mannan
RNA
TLR3: dsRNA
TLR7: ssRNA
TLR8: ssRNA
Expression
on cell surface or within endosomal copartment (TLR3,7,8,9)
Explain the importance of cofactors and structural features for TLR using TLR4 as an example
Lipid A portion of LPS bound by TLR4, but cofactor MD2 is important to induce conformational change of TLR4 that results in dimerization of the complex, MyD88 recruitment activates the MyD88 dependent pathways that acivates the NF-kappaB gene for an inflammatory response
Which TLRs are present in mice and humans?
Mice
TLR1-9 and TLR11-13
Humans
TLR1-10
Why is it helpful that some TLRs also recognize endogenous structures?
TLRs can also be activated by own dying cells, so TLRs recognizes molecules (DAMPs) that are only present during increased apoptosis rates e.g.
Cells release DNA/RNA bound to proteins, also Hsp or extracellular matrix proteins, other degradation products that can be recognized by TLRs
But this could also lead to autoimmunity inflammation
Downstream effects of TRL signalling (4)
proinflammatory cytokines
- TNF-a, IL-12, type 1 IFNs
- Chemokines
Antimicrobial effectors
- antimicrobial peptides
- ROS
Control of adaptive immune response
AG presentation
Trophic responses
Inhibitors of TLR signalling
Pathway inhibitors
- e.g. Myd88s, SOCS, IRAK-M
Antiinflammatory cytokines
- IL-10
- TGF-ß
Endotoxin tolerance
- preventation of exessive inflammation
TLR localization
Which PRRs and how do they trigger phagocytosis?
PRRs can bind different microbial patterns that leads to activation of intracellular domain to actively trigger phagocytosis
Examples
- Scavenger receptor (SR,MARCO)
- Mannan receptor (Dectin-2,Mannose receptor)
- ß-glycan receptor (Dectin-1)
- DEC 205
- Complement receptor (CR3,CR4)
- FC-gamma receptor
How do c type lectin receptor acitivate an immune response ?
C-type lectin receptors often have intracellular tyrosine-based signalling motif
After ligand binding this motif can be phosphorylated by tyrosin kinases and then work as binding motif for other adapter proteins like the Spleen tyrosine kinase
Activation of signalling pathways leads to transcription factor activation (e.g. NF-kappaB) to induce inflammatory response
Do sialic acid receptors play a role in TLR signalling?
Yes, they can immunoregulate the signalling, but mechanism isnt fully understood, seems that recruitment of phosphatases lead to inhibition of TLR downstream signals
