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89 Cards in this Set

  • Front
  • Back
What are macrophages derived from?
Peripheral blood monocytes
What happens when monocytes differentiate?
They leave the peripheral vasculature and differentiate into tissue macrophages.
What are 2 things that trigger macrophage activation?
-Ingestion of bacteria or bacterial products
-Cytokines or chemokines
What are lung macrophages?
alveolar
What are connective tissue macrophages?
histiocytes
What are liver macrophages?
kupffer cells
What are kidney macrophages?
Mesangial cells
What are brain macrophages?
microglial cells
What are bone macrophages?
osteoclasts
What are 3 types of uptake macrophages can do?
-Phagocytosis of large particles
-Endocytosis of small particles
-Endocytosis of receptor/ligands
What is Endocytosis of small particles called?
Pinocytosis
What is endocytosis of receptors and their ligands called?
Receptor mediated endocytosis
What changes occur in the macrophage to allow for phagocytosis?
The underlying cytoskeleton changes to loop out and around the particle being ingested.
What are 5 main functions of macrophages?
DRARE
-Detect microbial invasion
-Restrict microbial spread
-Assist in lymph activation
-Recruit immune cells
-Effect cell-mediated immunity
What are the 5 functional steps of phagocytosis?
1. Recognition
2. Uptake
3. Maturation
4. Killing
5. Antigen presentation
RUMKA
What is involved in bacterial recognition?
Antigen-receptor interactions
Do macrophages have only one receptor specific for each microbe?
NO - they can recognize bugs with many different host receptors.
What are 2 main ways that bacteria can be recognized by macrophages?
-PAMPS/PRRs
-Opsonization and Fc receptor
What does the specificity of interaction determine?
The subsequent steps that will occur in phagocytosis.
What will the binding of complement coated microbes to the C3b receptor on macrophages result in?
Induction of INOS and Phox activation to stimulate killing
What will binding of Mannose residues on microbes to the Mannose binding receptor (TL4) on macrophages result in?
Pathways that may allow the bacteria to survive within the cell.
What are 4 surface structures on bacteria that influence their being recognized by macrophages?
1. Pili
2. Surface proteins
3. Capsule
4. Flagella
How do pili influence bacterial recognition? What is an example of a bug that uses this mechanism?
Pili can undergo phase variation in response to variations in their environment - as in E. coli
How do surface proteins influence bacterial recognition? What is an example of a bug that uses this mechanism?
Changes in surface proteins can completely change the antigenic appearance of bugs like Borellia recurrentis
What disease is caused by borellia recurrentis?
Relapsing fever
How do Flagella influence bacterial recognition?
Flagellar expression can be regulated by the bacteria.
How do Capsules influence bacterial recognition? What is an example of a bug that uses this mechanism?
Capsules can mask the epitopes of LPS and PG on some Gram pos bacteria and allow them to resist phagocytosis.
So the 4 main types of macrophage receptors for bacteria are:
-PRRs
-LPS/LTA
-Plasma derived
-Membrane derived
What bugs have LPS?
What bugs have LTA?
LPS = gram neg
LTA = gram pos (lipotechoate)
How do extracellular pathogens avoid recognition?
By capsules
What are 3 examples of plasma derived receptors on macrophages?
-Collectins
-Pentraxins
-Complement
What are 4 examples of membrane-derived receptors on macrophages?
-C-type lectins
-Leucine rich protiens
-Scavenger receptors
-Integrins
What is an example of a C-type lectin?
Macrophage mannose receptor
What are 4 microbes that have mannose?
-Candida albicans
-Mycobacterium tuberculosis
-Pneumocystis carinnii
-HIV1
What is an example of a Leucine rich protein surface receptor on macrophages?
CD14
What are the microbial ligands for CD14?
LPS and LTA
Peptidoglycan
E. coli
What is an example of a Scavenger receptor on macrophages?
Scavenger receptor A type I
What are the microbial ligands for Scavenger receptor A type I?
LPS and LTA
B. subtilis
E. coli
What is an example of an integrin receptor on macrophages?
CR3
What are the microbial ligands for CR3?
-M. tuberculosis
-B. pertussis
-Leishmania
-H. capsulatum
What step occurs in phagocytosis after bacterial recognition?
Bacterial uptake
What are the 3 general steps of bacterial uptake?
1. Microbe/receptor induces signal transduction cascade
2. Cytoskeletal remodels by actin depolymerization and repolymerization
3. Bacterium internalized into a phagosome
What type of process is bacterial uptake normally?
Passive
What is required for non-phagocytic cells to take up bacteria?
The bugs have to actively induce their own uptake.
How does Salmonella typhimurium induce its uptake?
By a trigger mechanism
What is the active mechanism utilized by L. monocytogenes?
Zipper
What is involved in the Trigger mechanism?
-Major cytoskeletal remodeling
-Effector proteins
What is involved in the Zipper mechanism?
-Receptor mediated process
-Minimal cytoskeletal remodeling
-Bacterial sliding into cell
How does Francisella tularensis get into macrophages?
By looping phagocytosis
How does Legionella pneumophilia get into macrophages?
By coiling phagocytosis
What does Rickettsia do once it is phagocytosed?
It escapes the phagosome by degrading it.
What step occurs after bacterial uptake?
Maturation of the phagosomes that contain the bacteria.
What is the fun description of phagosome maturation?
It's like a train that rides around on microtubule train tracks, picking up cars that alter the phagosomal pH as it goes from periphery to perinuclear region.
What does the phagosome fuse with?
Endocytic vesicles
What do early endosomes display?
-Rab5
-Transferrin receptor
-Fluid phase markers (FPMs)
What do late endosomes display?
-Rab7
-EEA1
-M6PR
-Lamp1 and Lamp2
-H ATPase
-other FPMs
What do Phagolysosomes display?
-Cathepsin D
-LAP
-H ATPase
What is the pH of the phagosome at ingestion?
7
What is the pH of the phagosome after fusion with early endosomes?
6.5 - 6
What is the pH of the phagosome after fusion with late endosomes?
6 - 5
What is the final pH of the phagolysosome?
4-5
What are Intracellular bacteria able to do in macrophages?
Block or alter the steps in phagosome maturation
What are the 4 mechanisms for altering phagosome trafficking?
1. Survive/replicate in phagolysosomes
2. Escape/replicate in cytosol
3. Modulate endocytosis
4. Modulate membrane trafficking
What organism survives and replicates in phagolysosomes?
Coxiella
Is anything altered about the phagosome maturation with Coxiella living in it?
No - in fact maturation is accelerated!
What does Coxiella do within the phagolysosome?
Replicates to high numbers
How can Coxiella survive the phagolysosome?
It has mechanisms to resist the low pH and antimicrobial products, and actually they activate genes that allow the bug to survive.
What are 5 bugs that can escape from phagosomes?
-Rickettsia
-Shigella
-E. coli
-Listeria
-Francisella tularensis
Why do those bugs have to escape from phagosomes?
In order to be able to replicate.
How do the bugs escape from their phagosomes?
By expressing dedicated enzymes that degrade the phagosomal compartment
How do the microbes survive intracellularly?
-avoid fusing with lysosomes
-Cytosol is nice and nutrient rich
What 2 organisms exhibit cell-to-cell spread, and how?
Shigella and Listeria - by making actin comet tails
What 2 microbes alter the phagocytic pathway?
-Mycobacterium
-Salmonella
Why do Mycobacterium and Salmonella alter the phagocytic pathway?
To establish themselves a unique niche within the phagocyte.
How do mycobacteria establish a niche?
By preventing acidification by arresting the phagosome at an early stage.
How does Salmonella establish a niche?
It allows acidification of the phagosome, but survives the acid.
What are the stipulations for when alteration of the phagocytic pathway will work?
-Bacteria must be alive
-Macrophage must remain inactivated
How do bacteria arrest the phagosome at early stages?
By expressing proteins that subvert the normal maturation process.
How does Salmonella remain intracellularly?
By the formation of a spacious vacuole
What microbes survive intracellularly by entering different phagocytic pathways?
-Legionella
-Brucella
-Chlamydia
How is the phagocytic pathway utilized by Legionella/Brucella and Chlamydia different?
-It is not accessible to the endocytic network or lysosome fusion events
-It remains closely interacting with ER and golgi
What are the mechanisms of bacteria killing by lysosomes?
-iNOS
-NADPH oxidase
-Acidic pH
-PHox
-Defensins/Lysozyme
What can macrophages do after bacteria are killed?
-Activate and ahieve effector functions
-Process and present the microbe as antigen
What do activated macrophages secrete?
Cytokines
What cytokines do activated macrophages secrete?
IL1, TNF-alpha
IL6, 8, and 12
What are the effects of macrophage cytokine secretion?
-Lymphocyte recruitment and activation
-Cross activation of other immune cells
-Increased vascular permeability
What are the systemic effects of IL1 and IL6 production?
Fever and APR production
Wasting
Shock
What happens when macrophages are continuously stimulted?
Tissue injury and disease
How does mycobacterium cause so much damage to the host?
By inducing so much chronic inflammation.