Macrophages Flashcards
Bacteria can be divided into two groups based on where they live
- intracellular
- extracellular
extracellular bacteria
-these bacteria live outside the cell an cause disease
intracellular bacteria
-these bacteria live inside the host cell and cause disease
how do extracellular bateria resist killing by phagocytes
- avoid recognition by phagocytes
- inhibit phagocyte engulfment
- kill or damage phagocyte
How do extracellular pathogens avoid recognition by phagocytes
1.Colonizeregionsnotaccessibletophagocytes– unbrokenskin
2.Minimizeinflammatoryresponse‐ modifiedLPS
3.Inhibitphagocytechemotaxis– Streptococcalstreptolysin
4.Hideantigenicsurface– GroupAStrephyaluronicacidcapsul
e
5.Evadeopsonization – Staph.aureusProteinA
How do extracellular pathogens inhibit phagocyte engulfment
6.Producecapsuleorotheranti‐phagocyticdeterminantsonsurface–
HyaluronicacidcapsuleinGroupAStrep
How do extracellular pathogens kill or damage phagocytes
Secreteordeliverenzymesortoxinsthatinhibitordamagehostcell
– Pneumolysin inStreptococcuspneumoniae
How do intracellular pathogens resist killing by phagocytes
- Inhibitphagosome‐lysosomefusion:
- Surviveinsidephagolysosome:
- Escapefromphagosome:
How do intracellular pathogens inhibit phagocome-lysosome fusion
1.Secreteproteinsthatblockphagosomematuration– typeIII
secretionsysteminSalmonellatyphimurium
How do intracellular pathogens survive inside the pagolysosome
2.ResistdegradationbyacidicpH,produceenzymesableto
counteractROIandRNIradicals,etc – productionofKatG (catalase)
orSodA (superoxidedismutase)
How do intracellular pathogens escape from the phagosome
Secreteenzyme(s)thatdegradephagosomal membrane– LLLO
(Listeriolysin O)productioninListeriamonocytogenes
Benefits of being intracellular
Environmentusuallynutrientrich
Livewithinaprotectedniche
-shelteredfromimmunecomponents
‐ shelteredfrombacterialcompetitors
Limitations of being intracellular
Mustovercomehostbarriers Resistinnateandacquiredimmunecomponents Survivewithinhostileenvironment ‐pH,antimicrobialpeptides,reactive oxygen/nitrogenspecies,other bacteriocidal enzymes
Obligate intracellular pathogens
-live only within cell
Chlamydia
Rickettsiaspp.
Coxiella burnetii
Facultative intracellular pathogens
can live in or outside of the cells
Mycobacteriumtuberculosis Salmonellaspp. Brucella spp. Legionellapneumophila Shigella spp. Francisella tularensis Listeriamonocytogenes Escherichiacoli Yersiniaspp.
Brief review of macrophages
-• Firstlineofdefense‐innate immunity - Derivedfromperipheralblood monocytes -Leavevasculatureand differentiateintotissue macrophages -Activateduponingestionof bacteriaorbacterialproducts, alsoactivatedbycytokinesor chemokines
What do phagocytes including macrophages do
internalizeinertand
biologicalparticlesusingvariousmechanisms
-regardless of the mechanism used to take it up, it results in taking in the particle and putting in a membrane capsules called the phagosome
What are the five functional steps of phagocytosis
- Recognition
- Uptake
- Maturation
- Killing
- Antigen
Describe step 1 of phagocytosis
Bacterial recognition
Phagocytes recognize:
-components of the bacterial cell wall or membrane
-components of the immune system following opsonization
-bacteria can be recognized by multiple host receptors, and the specific interaction can define subsequent events in steps of phagocytosis
What are some things that phagocytes recognize
- peptidoglycan layer
- surface proteins
- flagellum
- pili
- capsules are how they attemtp to avoid this recogniztion
Capsules
mask the epitopes so that the bacteria isn’t recognized by the phagocyte
Macrophages express a variety of receptors
- PRRs recognize conserved bacterial structures including LPS (Gram -) and LTA (gram +)
- receptors that recognize plasma-derived molecules deposited on bacterial surface (collectins, pentraxins, comlemetn
- receptors (C-type lectins, leucine-rich proteins) that recognize other signature elements on bacteria
- receptor engagement generates different host cell responses depending on receptor. Multiple surface receptors may be engaged by single bacterium
how do extracellular pathogens avoid recognition
capsules
Describe step 2 in the steps of phagocytosis
- recognition between ligand and receptor initiates transmembrane activation cascade-signal transduction
- surface structure remodeled by polymerizing and depolymerizing actin and other cytoskeletal components
- bacteria is internalized within a membrane bound compartment termed a phagosome
- internalization process into a phagocytic cells is usually passive; however some bacteria influence their own internalization
- some bacteria employ specialized entry mechanisms to avoid normal phagosome maturation steps
Describe the process of remodeling of macrophage membrane
- in macrophages this is a passive process. Does not require that bacteria induce their own uptake
- plasma membrane remodeling occurs only at site of recognition
- plasma membrane extensiosn-due to loacal actin polymerization
However some bacteria undergo specialized phagocytosis
- looping phagocytosis: Francisella tularensis causes phagocyte arm to wrap around
- coiling phagocytosis: Legionella penumophila causes the phagocyte to spiral around it
What does entry into non-phagocytic cells require
bacteria to induce their own uptake
Describe the trigger mechanism and which organism does it
Salmonella typhimurium
- Major membrane perturbation
- major cytoskeletal remodeling
- promoted by bacterial effector proteins injected into the host cell
Describe the zipper mechanism and which organism does it
Listeria monocytogenes
- minimal cytoskeletal remodeling
- bacteria “slide” into cell. Also involves bacterial proteins (causes massive membrane blebbing)
Step 3 of Phagocytosis
Maturation of bacteria containing phagosomes
- maturation proceeds by fusion with endocytic vesicles
- depending on the proteins present on the surface of the phagosome they are termed “early” or “late”endosomes
- Early endosomes display: Rab 5, Tfr, and FPM
- Late endosome display: Rab7, EEA1, M6PR, LAMP-1, and 2, and H ATPase and other FPM.
- phagolysosomes display Cathepsin D, LAP and H ATPase
What is the cytoskeletal component that allows maturation of the phagosome from the periphery to the rperinuclear region
Microtubules
Describe the differences between phagosomal vesicles
The phagolysosome has way more proteins etc on its surface. for example it has way more H ATPases bc it is needs to make its internal environment super acidic to KILL bacteria
Phagogosome Maturation
Dynamic series of fusion events leading to phagosome acidification and fusion of phagosome with the lysosome
bacteria and the phagosome maturation process
intracellular bacteria can block or alter steps in the maturation process
How does macrophage activation influence the baility of bacteria to alter phagosome maturation
-bacteria want to stop phogosome maturation, but macrophage activation reduces the ability of bacteria to alter maturation
How do bacteria alter phagosome trafficking
- They survive and replicate in the phagolysosome
- Escape and replicate in the cytosol
- Modulate the endocytic pathway
- Alternative trafficking pathway
Which bacteria alter phagosome trafficking by surviving and replicating in the phagolysosome
-Coxiella spp.
It is able to replicate in the phagolysosome! It isn’t killed in there
What bacteria escape and replicate in the cytosol
- Rickettsia
- Shigella
- Escherichia coli
- Listeria
- Francisella
they create a protein that destroys the phagosomal membrane so they can be FREE in the cytosol to replicate
Which baterica modulate the endocytic pathway
- Mycobacterium
- Salmonella
-they prevent he phagosome from fusing with the lysozome `
Which bacteria make an alternative trafficking pathway
- Legionella
- Brucella
- Chlamydia
How do lysosomes kill bacteria
- oxygen dependent killing:
- iNOS generated nitric oxide
- NADPH oxidase generates superoxide
-Oxygen independent
Describe step 5 of phagocytosis
processing of bacterial antigens
- antigen degraded to oligopeptides (13-18 amino acids)
- Binding to Class I or Class II MHC and antigen presentation on surface
- Stimulation of T-cell responses
- Degraded material is exocytosed and can be presented by nearby APC
How does bacterial internalization activate Macrophages
- induce cytokine production which is beneficial when released in moderation for short duration
- mediate lymphocyte recruitment and macrophage activation
- mediate cross activation of other immune cells
- increase vascular permeability
What are some not so good consequences of bacteria ingestion by macrophages
- tissue injury and disease upon continuous stimulation
- ROI, RNI and hydrolytic enzymes lead to tissue damage
- TNFa and IL1 lead to fever, wasting and septic shock
- persistant infections lead to chronic inflammation
- phagocytes contribute to autoimmune diseases
- can act as trojan horse to disseminate pathogens
what are the two categories of intracellular pathogens
- obligate or faculatative
- a number of disease causing bacteria are intracellular pathogens of macrophages
Uptake of bacteria by macrophages is a multi step process that involves:
- recognition
- internalization
- maturation
- killing
- antigen presentation
Intracellular pathogens have evolved strategies that enhance their survival within phagocytic cell. these include
- the ability to resist acidic pH and lysosome degradation enzymes
- escape from the phagosome
- prevention of phagosome maturation
- alterations in the trafficking pathway
What is a bad thing that can happen from macrophage activation
macrophage activation can lead to detrimental host response that includes overstimulation of immune system
