Bacterial Interaxns w/ Macrophages
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| What is the first line of defense in innate immunity? | Macrophages
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| Where are macrophages derived? | From peripheral blood monocytes which leave vasculature and differentiate into tissue macrophages
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| How are macrophages activated? | - Upon ingestion of bact./bact. products - By cytokines or chemokines
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| What are the names of macrophages in various tissues? 1. lung 2. CT 3. liver 4. kidney 5. brain 6. bone | 1. alveolar
2. histiocytes
3. Kupffer cells
4. mesangial cells
5. microglial cells
6. osteoclasts
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| What are the 5 functions of macrophages? | 1. detect microbial invasion
2. restrict microbial spread
3. recruit immune cells
4. act as accessory cells in lymphocyte activation
5. act as effector cells in cell-mediated immunity
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| What are the 5 steps of phagocyotosis? | 1. recognition
2. uptake
3. maturation
4. killing
5. Ag presentation
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| Describe the bact. recognition step 1 of phagocytosis. | Bact. can be recognized by multiple host receptors and involves common Ag-receptor interaxns b/w bact. and macrophage
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| What are the surface structures of GRAM + bact. that influence recognition? | capsule, PG layer, surface proteins (change Ag presentation in Borrelia recurrentis), flagellum
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| What are the surface structures of GRAM - bact. that influence recognition? | outer membrane, capsule (masks epitopes), pili (phase variation in E. Coli pap), PG layer, flagellum (regulated expression)
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| What are other macrophage-bact. interaxns? | - use PRR's, LPS in Gram - and Gram +, plasma derived, membrane-derived, receptors generate diff host responses, multiple macrophage surface receptors may recognize molecules on single bact., EC pathogens avoid recognition capsules
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| What are 4 types of common membrane-derived receptors? | 1. C-type lectins (eg. macrophage mannose receptor)
2. leu-rich proteins (eg. CD14)
3. scavenger receptors (eg. scavenger receptor A type 1)
4. integrins (eg. CR3)
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| Describe the bact. uptake step 2 of phagocytosis. | - Recognition b/w ag and receptor starts a transmembrane activation cascade-signal transduction. The surface structure is remodeled by depolymerizing and repolymerizing actin. Bact. is internalized w/i a phagosome.
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| How does bact. enter non-phagocytic cells when bact. internalization is not passive and is active? | 1. trigger mech
2. zipper mech
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| Describe the Trigger Mech. - What induces? - Cytoskeleton remodeling? - What promotes? - An eg. | - pathogen-induced
- involves major cytoskeleton remodeling
- promoted by effector proteins
- Salmonella typhimurium
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| Describe the Zipper Mech. - What induces? - Cytoskeleton remodeling - How? - An eg. | - receptor-mediated
- minimal cytoskeleton remodeling
- bact. slide into cell
- Listeria monocytogenes
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| What is a phagosome? | A membrane-bound compartment in which bact. is internalized, usu. passive.
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| Describe the bact. maturation step 3 of phagocytosis. | - Phagosome acidifies and fuses w/ endocytic vesicles to form "early" or "late" endosomes, depending on the proteins present on the vesicle surface.
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| What allows the maturation of the phagosome from the periphery to perinuclear region? | Microtubules
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| What do "early" endosomes display? | - Rab5
- Transferrin receptor (Tfr)
- other fluid phase markers (FPM)
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| What do "late" endosomes display? | - Rab7
- EEA1
- M6PR
- LAMP-1 and -2
- H+-ATPase
- other FPM
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| What do phagolysosomes display? | - Cathepsin D
- LAP
- H+-ATPase
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| What can block or alter steps in maturation process of the phagosome? | IC bact.
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| What are 4 mechanisms and eg. of each that alter phagosome trafficking? | 1. bact. survive and replicate in phagolysosome
2. bact. escape and replicate in cytosol
3. modulate endocytic pathway
4. alternative membrane trafficking
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| Describe mech 1. | - Phagosome completely matures and fuses with endocytic organelles, accelerating maturation into phagolysosome where it replicates in high numbers.
- Has mechs to resist low pH and other antimicrobial products generated
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| Describe mech 2. | - Initially ingested in phagosome, but expresses enzymes to degrade phagosomal compartment and avoids fusion with lysosome. The cytosol is nutrient-rich for replication.
- Cell-to-cell spread
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| Describe mech 3. | - Phagosomes are arrested at an early stage. Bact. have proteins that subvert the normal maturation process.
- Occurs only w/ live bact. and unactivated macrophages.
- Mycobacterium has no acidification.
- Salmonella survives acid and forms vacuole.
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| Describe mech 4. | - The phagocytic compartment isn't accessible to endocytic network so no lysosome fusion events. There is a close interaxn w/ ER and Golgi.
- May be related to entry mechs where novel receptors and/or processes are used for internalization.
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| Describe the bact. killing step 4 of phagocytosis. | - The phagocytic compartment isn't accessible to endocytic network so no lysosome fusion events. There is a close interaxn w/ ER and Golgi.
- May be related to entry mechs where novel receptors and/or processes are used for internalization.
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| Describe the bact. Ag-recognition step 5 of phagocytosis. | Ag are degrated into oligopeptides of 13-18 aa then they bind to Class II MHC and are presented by nearby APC. The Ag presentation on cell surface stimulates T-cells.
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| What do activated macrophages secrete? | - IL-1
- TNF alpha
- IL-6
- IL-8
- IL-12
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| What are the local and systemic effects of IL-1 secretion? What are the local and systemic effects of IL-1 secretion? | - Local: activates vascular endothelium, activates lymphocytes, local tissue destruction, increases access of effector cells
- Systemic: fever, production of IL-6
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| What are the local and systemic effects of TNF-alpha secretion | - Local: activates vascular endothelium and increases vascular permeability which leads to increased entry of IgG, completment and cells to tissues and increased fluid drainage to lymph nodes
- Systemic: fever, mobilization of metabolites, shock
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| What are the local and systemic effects of IL-6 secretion? | - Local: lymphocyte activation, increased Ab production
- Systemic: fever, induces acute-phase protein production
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| What are the local and systemic effects of IL-8 secretion? | - Local: chemotactic factor recruits neutrophils, basophils, and T cells to site of infxn
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| What are the local and systemic effects of IL-12 secretion? | - Local: activates NK cells, induces the differentiation of CD4 into TH1
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| What are consequences of bacteria internalization? | - Beneficial when released in moderation
- Lymphocyte recruitment and activation
- Cross-activation of other immune cells
- Increased vascular permeability
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| How can a macrophage response damage the host? | - if continuously stim., can cause tissue dz
- ROI, RNI, hydrolytic enzymes damage tissue
- TNF-alpha and IL-1 can cause fever, wasting, and septic shock
- chronic inflammation
- phagocytes contribute to autoimmune dz
- can disseminate pathogens
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| An eg. of organism that survive and replicate in phagolysosome. | Coxiella
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| An eg. of organism that escapes and replicates in cytosol. | Rickettsia, Shigella, E. Coli, Listeria
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| An eg, of organism that modulates endocytic pathway. | Myobacterium, Salmonell
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| An eg. of organism that alternates membrane trafficking. | Legionella, Brucella, Chlamydia
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