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26 Cards in this Set

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Phagocytes
* specialized cells that carry out the process of phagocytosis

- phagocytosis = cellular eating

Ex. neutrophils, macrophages
Chemotaxis
* process by which a cell can undergo directional movement controlled by a chemical gradient

* used by neutrophils to look for bacteria
Chemoattractants
1) chemokine, cytokines: secrete by immune cells, chemicals given off during inflammation

2) bacterial proteins like fMLP

3) complement components like c5a
Chemoattractant Receptors
* have a seven transmembrane domain

* coupled to a signalling cascade that consists of a heterotrimeric GTP binding protein
Heterotrimeric GTP Binding Protein
* consists of three subunits:
- α (binds to GTP)
- β, γ (no binding to GTP)
Gs protein (stimulatory G protein)
receptor → Gs → activates adenylate cyclase (ATP → cAMP + PPi → → → downstream responses)

* target of cholera toxin: locks Gs into GTP bound form = constant production of cAMP
Gi protein (inhibitory G protein)
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
Rho Family of GTPases
* consists of monomeric GTPases

* mediates cell migration

* exists in two forms:
- GDP (inactive)
- GTP (active)

* GDP → GTP via GEF
* GTP → GDP via GAP
Steps in Cell Migration
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
Actin
* 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)
Actin Polymerization (monomers → polymers)
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
Rac
* responsible for the forward movement of the front of the cell

* Rac GTPase → WASP → Arp 2/3 complex → nucleation and branching of actin filaments
WASP
* Wiskott-Aldrich Syndrome Protein

* effector protein

* syndrome patients get increased infections because immune cells can't migrate or phagocytose
Integrins
* 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
Phalloidin
* drug that binds actin filaments

* prevents depolymerization
Cytochalasin
* inhibits actin polymerization and depolymerization

* if its addition inhibits bacteial entry, then entry of the bacterim is an actin-dependent process
Stages of Phagocytosis
1) Recognition of Pathogen and Binding

2) Internalization

3) Phagosome Maturation

4) Killng and Degradation of Pathogen
Recognition of Pathogen and Binding
* 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
Internalization
* 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
Zipper Mechanism
* non-phagocytic cells (ex. epithelial cells) req that pathogens induce their own phagocytosis

* bacterium only polymerizes actin in the immediate area
Trigger (Splash) Mechanism
* non-phagocytic cells (ex. epithelial cells) req that pathogens induce their own phagocytosis

* bacterium polymerizes actin all over the cell
Maturation of Phagosome
* 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
Bafilomycin
* inhibits vacuolar ATPase
= inhibits acidification
Antimicrobial Components of Lysosome
* low pH

* ROIs

* toxic nitric acid

* enzymes that degrade bacterial proteins
- nucleases, proteases, lipases, glycosidases

* iron competiors (lactoferrin)

* antimicrobial peptides (defensins)
Strategies for Surviving Phagocytosis
* 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
Autophagy Pathway
* 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