Macrophages Flashcards by Allison Cotter

Bacteria can be divided into two groups based on where they live

intracellular

- extracellular

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extracellular bacteria

-these bacteria live outside the cell an cause disease

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intracellular bacteria

-these bacteria live inside the host cell and cause disease

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how do extracellular bateria resist killing by phagocytes

avoid recognition by phagocytes
inhibit phagocyte engulfment
kill or damage phagocyte

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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

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How do extracellular pathogens inhibit phagocyte engulfment

6.Producecapsuleorotheranti‐phagocyticdeterminantsonsurface–
HyaluronicacidcapsuleinGroupAStrep

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How do extracellular pathogens kill or damage phagocytes

Secreteordeliverenzymesortoxinsthatinhibitordamagehostcell
– Pneumolysin inStreptococcuspneumoniae

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How do intracellular pathogens resist killing by phagocytes

Inhibitphagosome‐lysosomefusion:
Surviveinsidephagolysosome:
Escapefromphagosome:

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How do intracellular pathogens inhibit phagocome-lysosome fusion

1.Secreteproteinsthatblockphagosomematuration– typeIII
secretionsysteminSalmonellatyphimurium

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How do intracellular pathogens survive inside the pagolysosome

2.ResistdegradationbyacidicpH,produceenzymesableto
counteractROIandRNIradicals,etc – productionofKatG (catalase)
orSodA (superoxidedismutase)

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How do intracellular pathogens escape from the phagosome

Secreteenzyme(s)thatdegradephagosomal membrane– LLLO

(Listeriolysin O)productioninListeriamonocytogenes

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Benefits of being intracellular

Environmentusuallynutrientrich
Livewithinaprotectedniche

-shelteredfromimmunecomponents
‐ shelteredfrombacterialcompetitors

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Limitations of being intracellular

Mustovercomehostbarriers
Resistinnateandacquiredimmunecomponents
Survivewithinhostileenvironment
‐pH,antimicrobialpeptides,reactive
oxygen/nitrogenspecies,other
bacteriocidal enzymes

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Obligate intracellular pathogens

-live only within cell
Chlamydia
Rickettsiaspp.
Coxiella burnetii

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Facultative intracellular pathogens

can live in or outside of the cells

Mycobacteriumtuberculosis
Salmonellaspp.
Brucella spp.
Legionellapneumophila
Shigella spp.
Francisella tularensis
Listeriamonocytogenes
Escherichiacoli
Yersiniaspp.

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Brief review of macrophages

-• Firstlineofdefense‐innate
immunity
- Derivedfromperipheralblood
monocytes
-Leavevasculatureand
differentiateintotissue
macrophages
-Activateduponingestionof
bacteriaorbacterialproducts,
alsoactivatedbycytokinesor
chemokines

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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

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What are the five functional steps of phagocytosis

Recognition
Uptake
Maturation
Killing
Antigen

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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

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What are some things that phagocytes recognize

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peptidoglycan layer
surface proteins
flagellum
pili
capsules are how they attemtp to avoid this recogniztion

Capsules

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mask the epitopes so that the bacteria isn’t recognized by the phagocyte

Macrophages express a variety of receptors

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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

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capsules

Describe step 2 in the steps of phagocytosis

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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

1. They survive and replicate in the phagolysosome 2. Escape and replicate in the cytosol 3. Modulate the endocytic pathway 4. 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

Macrophages Flashcards

(48 cards)