Pattern Recognition Flashcards

1
Q

Describe the types of phagocytic cell

A

• Macrophages → mature from monocytes that migrate into tissue. Major phagocystic population in normal tissues
• Granylocytes → Ns Es, Bs. Ns have the greates phagocytic activity. First to be involved in innate immunity
• DCs → arise from myeloid and lymphoid progenitors in the bone marrow. Migrate through blood to peripheral lymphoid organs. Their primary role is not ingestion, but antigen presentation.
− Conventional DCS → process ingested microbes and generate antigen that can activate T cells (bridge between innate and adaptive immunity)
− Plasmacytoid DCs → produce antiviral interferons

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2
Q

List some potential PAMPs

A
  • mannose-rich oligosaccharides
  • peptidoglycans
  • LPS
  • unmethylated repeates of the dinucleotide CpG (often methylated in mammalian DNA)
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3
Q

Dectin-1 PRR

A
  • Includes several members of the C-type lectin family

* Recognises B-1,3-linked glucans (polymers of glucose) – common components of fungal cell walls

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4
Q

Mannose receptor PRR

A
  • Another C-type lectin
  • recognizes mannoyslated ligands, including some on fungi, bacteria and viruses
  • thought to function mainly as a clearance receptor for host glycoproteins such as B-glucoronidace and lysosomal hydrolases (raised during inflammation)
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5
Q

Scavenger receptor PRR

A
  • Recognise various anionic polymers and acetylated LDLs.
  • Class A scavenger receptors (SR-A I, SR-A II and MARCO) all bind various bacterial cell wall structures and help internalize bacteria
  • Class B scavenger receptors bind HDLs and internalize lipids
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6
Q

GPCRs as PRRs

A
  • Direct responses to anaphylatoxins and chemokines – recruiting phagocytes to the site of infection and promoting inflammation
  • the fMLP receptor is a GPCR that senses the presence of bacteria by recognizing the fMet residue in bacterial polypeptides.
  • Bacterial polypeptides binding to this receptor activate signaling pathways that direct the cell to move towards the most concentrated source of the ligand.
  • Signalling through fMLP also induces the production of microbicidal ROS in the phagolysosome
  • The C5a receptor triggers similar responses to the fMLP
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7
Q

Describe Toll signalling in Drosophila

A

• Toll gene first gene found to be linked to the innate immune system
• Toll itself isn’t a PRR – relies on several families of pathogen detector proteins →eg) peptidoglycan recognition proteins (PGRPs) and gram-negative binding proteins
• PGRP recognize components of bacterial cell walls
• GNBPs recpgnise B-1-3-linked glucans and involved in the recognition and fungi
− They interact with a serine protease called Grass which leads to proteolytic cleavage of Spatzle.
− This induces a conformational change in Spatzle,
− One of the cleaved Spatzle fragments forms a homodimer, and induces the dimerization and activation of Toll to induce the antimicrobial response.

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8
Q

Describe ligand binding to mammalian TLRs

A

• Unlike Drosophila toll, which does not recognize pathogen products directly, X-ray crystal structures of 3 mammalian dimeric TLRs show at least some of them make direct contact with microbial ligands.
• Ligand binding induces the formation of homo/heterodimers.
− TLR1:TLR2 → triacyl lipopeptid binds two lipid chains to the convex surface of TLR-2, and one lipid chain to the convex surface of TLR-1. Dimerisaiton brings the cytoplasmic TIR domains of the TLR chains in close proximity to initiate signaling
− TLR5 → recognizes a conserved site on flagellin that is buried and inaccessible in the assembled flagellar filament. So the receptor is only activated by monomeric flagellin
− TLR3 → recognizes dsRNA, a replicative intermediate of many virus. It encounters the TLR on the endosome after internalization by phagocystosis. The two-fold symmetry of dsRNA allows it to bind to two TLR-3 domains, inducing dimerization.

Not all TLRs bind their ligand so directly!
− TLR4 → uses an accessory protein MD-2. MD-2 traffics TLR to the cell surface, and is essential for LPS recognition.

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9
Q

What are the effects of mammalian TLR activation?

A

• Induces a diverse range of intracellular responses that result in the production of inflammatory cytokines, chemotactic factors, antimicrobial peptides and antiviral cytokines IFN-a, IFN-b and type I interferons.
• Signalling is activated by the ligand induced dimerization
− This brings their TIR domains close together and allows them to interact with the TIR domains of cytoplasmic adaptor molecules that initiate intracellular signaling. There are 4 such adaptors:
− myD88
− MAL
− TRIF
− TRAM
− Different TLRs interact with different combinations of these adaptors.
− These adaptors recruit IRAK
− This activates the ubituinin ligase TRAF6
− TRAF-6 and NEMO are polyubiquitinated, creating a scaffold for activation of TAK1
− TAK1 assocaites with IKK and phosphorylates IKKB, which phosphorylates IkB
− IkB is degraded, releasing NFkB into the nucleus.
− The ability of TLRs to activate NFkB is crucial to their role of altering the immune system to the presence of bacterial pathogens
− Inactivating mutations in IRAK or NEMO cause immunodeficiency

− As well as NFkB, interferon regulatory factors may be activated (by TLR7, 8 and 9)
− NFkB or IFN activation means both antivral and antibacterial responses can be initiated

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10
Q

Describe the NOD subfamily of NLRs

A
  • The NOD subfamily has an amino terminal caspase-recruitment domain (CARD).
  • CARD is related to the death domain in myD88 and can dimerise with CARD proteins on other domains.

• NOD proteins recognize fragments of bacterial cell wall peptidoglycans.
• When NODs recognize their ligand, it recruits the CARD containing ser/thr kinase RIPK2.
− RIPK2 activates TAK1, which associated with IKK, phosphorylates IKKB, which phosphorylates IkB → active NFkB.
− NFkB then induces expression of genes for inflammatory cytokines
• NOD proteins are expressed in cells routinely exposed to bacteria (barrier forming epithelial cells, and macrophages and DCs) → consistent with this, loss of function of NOD leads to Crohns.

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11
Q

Describe the NLRP subfamily of NLRs

A
  • These have a pyrin domain
  • Structurually related to CARD and interact with other pyrin domains
  • NALP3 is the best characterized
  • Important sensor of cellular damage/stress
  • Assembles with caspase 1 to form the inflammasome
  • Caspase 1 required for the proteolytic cleavage of some pro-inflammatory cytokines
  • In healthy cells, the LRR of NALP3 is bound to accessory proteins that keep it in a monomeric state. It is thought efflux of K+ (commonly occurring in stressed cells) cause dissociation of these accessory proteins.
  • Not yet clear whether NLRPs function as receptors for specific microbial products
  • The inflammsome has been implicated in some inflammatory diseases:
  • Gout causes inflammation because urate chrystals activate the inflammasome
  • Mutations in the NOD domain of NALP3 can cause inappropriate inflammasome activation, causing some inherited autoinflammatory disease
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12
Q

Describe the RIG-I-like helicases

A
  • TLR3, 7 and 9 can detect viral RNA and DNA, but they interact primarily with extracellular material entering the endocytic pathway rather than nucleic acids present in the cytoplasm of a virus-infected cell.
  • Cytoplasmic viral RNAs are sensed by the RLHs
  • Have a helicase-like domain that binds to viral RNAs
  • Two amino terminal CARD domains interact with adaptor proteins and activate signaling when viral RNAs are bound.
  • RIG-I was the first sensor to be discovered → induces production of type 1 interferons
  • When RIG-I detects a viral RNA ligand in the cytosol, its CARD domain interacts with a CARD containing adaptor called MAVS that is attached to the outer mitochondrial membrane
  • This activates a signaling pathway that involes TRAF-6 and activates TBK1
  • This leads to the activation of IFR3 and production of IFN-a and IFN-b
  • Activation of RIG-I can also induce cytokine production through a signaling pathway that involves the adaptor protein FADD
  • This activates caspases 8 and 10, which leads to the activation of IKK and NFkB, inducing production of pro-inflammatory cytokines.
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