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26 Cards in this Set
- Front
- Back
Phagocytes
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* specialized cells that carry out the process of phagocytosis
- phagocytosis = cellular eating Ex. neutrophils, macrophages |
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Chemotaxis
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* process by which a cell can undergo directional movement controlled by a chemical gradient
* used by neutrophils to look for bacteria |
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Chemoattractants
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1) chemokine, cytokines: secrete by immune cells, chemicals given off during inflammation
2) bacterial proteins like fMLP 3) complement components like c5a |
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Chemoattractant Receptors
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* have a seven transmembrane domain
* coupled to a signalling cascade that consists of a heterotrimeric GTP binding protein |
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Heterotrimeric GTP Binding Protein
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* consists of three subunits:
- α (binds to GTP) - β, γ (no binding to GTP) |
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Gs protein (stimulatory G protein)
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receptor → Gs → activates adenylate cyclase (ATP → cAMP + PPi → → → downstream responses)
* target of cholera toxin: locks Gs into GTP bound form = constant production of cAMP |
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Gi protein (inhibitory G protein)
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receptor → Gi → Rho family
* leads to the ability for neutrophils to target bacteria via chemotaxis * target of pertusin toxin: inhibits Gi = prevents activation of pathway = inhibits chemotaxis |
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Rho Family of GTPases
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* consists of monomeric GTPases
* mediates cell migration * exists in two forms: - GDP (inactive) - GTP (active) * GDP → GTP via GEF * GTP → GDP via GAP |
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Steps in Cell Migration
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1) polarization (Cdc42)
- cell must have front and rear - front faces high [ ] of chemoattractant 2) protrusion (Rac) - pseudopodium extends membrane forward 3) adhesion (Rho) - pseudopodium attaches itself to surface via focal adhesion 4) translocation (Rho) - cell squeezes itself at read to move cell forward 5) de-adhesion - cell leaves old focal adhesion behind |
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Actin
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* cell migration mediated by actin cytoskeleton
* exists in two forms: - monomer form - polymer form: non-covalent attachment of monomers into filament-like structure (major fxnal unit) |
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Actin Polymerization (monomers → polymers)
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1) nucleation: monomers come together to form a seed; filaments created
2) elongation: more monomers are added to the ends * nucleation and elongation drive the process of protrusion: generate the force to push a cell fwd as it moves 3) steady state: constant polymerization and depolymerization |
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Rac
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* responsible for the forward movement of the front of the cell
* Rac GTPase → WASP → Arp 2/3 complex → nucleation and branching of actin filaments |
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WASP
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* Wiskott-Aldrich Syndrome Protein
* effector protein * syndrome patients get increased infections because immune cells can't migrate or phagocytose |
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Integrins
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* contained inside the focal adhesions
* activated by Rho during adhesion in a bidirectional manner * transmembrane receptor proteins - outside te cell they interact with ECM (cells are sitting on them) - inside the cell they interact with actin |
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Phalloidin
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* drug that binds actin filaments
* prevents depolymerization |
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Cytochalasin
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* inhibits actin polymerization and depolymerization
* if its addition inhibits bacteial entry, then entry of the bacterim is an actin-dependent process |
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Stages of Phagocytosis
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1) Recognition of Pathogen and Binding
2) Internalization 3) Phagosome Maturation 4) Killng and Degradation of Pathogen |
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Recognition of Pathogen and Binding
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* opsonization: bacterial surface opsonized (coated) with molecules that allow it to be recognized
* opsonins: molecules that coat the surface of bacteria and allow them to be phagocytosed - rcognized by receptors Ex. complement proteins (C3b) and antibodies |
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Internalization
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* phagocyte grabs on and internalizes the particles
activation of receptors that recognize the bacterium ↓ Rho family ↓ Cdc42 and Rac activation ↓ WASP protein ↓ Arp 2/3 complex ↓ actin polymerizes beneath phagocyte and extends the surface to grab onto bacterium and pull it into cell |
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Zipper Mechanism
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* non-phagocytic cells (ex. epithelial cells) req that pathogens induce their own phagocytosis
* bacterium only polymerizes actin in the immediate area |
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Trigger (Splash) Mechanism
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* non-phagocytic cells (ex. epithelial cells) req that pathogens induce their own phagocytosis
* bacterium polymerizes actin all over the cell |
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Maturation of Phagosome
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* once it gets into the cell, bacterium is in phagosome
* phagosome undergoes maturation, which involves acquisition of bactericidal components * not a linear process: involves constant budding and fusion early endosome ↓ multivesicular body ↓ late endosome ↓ lysosome * maturation accompanied by increasing acidification - vacuolar ATPase is an ATP-hydrolyzing enzyme that pumps protons into the lumen of compartment |
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Bafilomycin
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* inhibits vacuolar ATPase
= inhibits acidification |
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Antimicrobial Components of Lysosome
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* low pH
* ROIs * toxic nitric acid * enzymes that degrade bacterial proteins - nucleases, proteases, lipases, glycosidases * iron competiors (lactoferrin) * antimicrobial peptides (defensins) |
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Strategies for Surviving Phagocytosis
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* relevant to intracellular pathogens
1) escape: get out of phagosome ASAP ex. Listeria escapes to cytosol and lives there 2) prevent maturation of endosomal compartment into a lysosomal compartment - manipulate the transport of cargo into endosomal compartment 3) survive in the lysosome |
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Autophagy Pathway
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* bacteria that have escaped into the cell may be subjected to an internal phagocytic pathway
* intracellula pathway normally involved in degrading intracellular components ex. organelles in need of degradation * involves sequestration and maturation |