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MICRO

Bacterial Interaxns w/ Macrophages

QuestionAnswer
What is the first line of defense in innate immunity? Macrophages
Where are macrophages derived? From peripheral blood monocytes which leave vasculature and differentiate into tissue macrophages
How are macrophages activated? - Upon ingestion of bact./bact. products - By cytokines or chemokines
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
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
What are the 5 steps of phagocyotosis? 1. recognition 2. uptake 3. maturation 4. killing 5. Ag presentation
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
What are the surface structures of GRAM + bact. that influence recognition? capsule, PG layer, surface proteins (change Ag presentation in Borrelia recurrentis), flagellum
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)
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
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)
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.
How does bact. enter non-phagocytic cells when bact. internalization is not passive and is active? 1. trigger mech 2. zipper mech
Describe the Trigger Mech. - What induces? - Cytoskeleton remodeling? - What promotes? - An eg. - pathogen-induced - involves major cytoskeleton remodeling - promoted by effector proteins - Salmonella typhimurium
Describe the Zipper Mech. - What induces? - Cytoskeleton remodeling - How? - An eg. - receptor-mediated - minimal cytoskeleton remodeling - bact. slide into cell - Listeria monocytogenes
What is a phagosome? A membrane-bound compartment in which bact. is internalized, usu. passive.
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.
What allows the maturation of the phagosome from the periphery to perinuclear region? Microtubules
What do "early" endosomes display? - Rab5 - Transferrin receptor (Tfr) - other fluid phase markers (FPM)
What do "late" endosomes display? - Rab7 - EEA1 - M6PR - LAMP-1 and -2 - H+-ATPase - other FPM
What do phagolysosomes display? - Cathepsin D - LAP - H+-ATPase
What can block or alter steps in maturation process of the phagosome? IC bact.
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
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
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
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.
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.
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.
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.
What do activated macrophages secrete? - IL-1 - TNF alpha - IL-6 - IL-8 - IL-12
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
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
What are the local and systemic effects of IL-6 secretion? - Local: lymphocyte activation, increased Ab production - Systemic: fever, induces acute-phase protein production
What are the local and systemic effects of IL-8 secretion? - Local: chemotactic factor recruits neutrophils, basophils, and T cells to site of infxn
What are the local and systemic effects of IL-12 secretion? - Local: activates NK cells, induces the differentiation of CD4 into TH1
What are consequences of bacteria internalization? - Beneficial when released in moderation - Lymphocyte recruitment and activation - Cross-activation of other immune cells - Increased vascular permeability
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
An eg. of organism that survive and replicate in phagolysosome. Coxiella
An eg. of organism that escapes and replicates in cytosol. Rickettsia, Shigella, E. Coli, Listeria
An eg, of organism that modulates endocytic pathway. Myobacterium, Salmonell
An eg. of organism that alternates membrane trafficking. Legionella, Brucella, Chlamydia
Created by: kelgsny