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IAHI Block 2 > 8 - Interactions with Macrophages > Flashcards

8 - Interactions with Macrophages Flashcards

1
Q

What bacteria subdivisions can be used to describe location within the host?

A

Extracellular bacteria: live outside host cells and cause disease

Intracellular bacteria: can be cytoplasmic or phagosomal (within a membrane bound compartment): these live inside the host cells and cause disease.

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2
Q

What are three examples of extracellular bacteria?

A

Staphylococcus
Streptococcus
Pseudomonas

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3
Q

What are strategies used by extracellular pathogens to resist killing by phagocytes?

A

Avoid recognition by phagocytes

Inhibit phagocyte engulfment

Kill or damage phagocytes

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4
Q

How do extracellular pathogens avoid recognition by phagocytes?

A
  1. Colonize regions not accessible to phagocytes like unbroken skin
  2. Minimize inflamm response with modified LPS
  3. Inhibit phagocyte chemotaxis-Streptococco streptolysin
  4. Hide antigenic surface-group A strep via hyaluronic acid capsule
  5. Evade opsonization - staph aureus protein A
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5
Q

How do extracellular pathogens inhibit phagocyte engulfment? How do they kill or damage phagocytes?

A

Inhibit engulfment: Produce capsule or other determinants on surface such as hyaluronic acid capsule in group A strep.

Kill or damage phagocytes: secrete or deliver enzymes or toxins that inhibit or damage cells such as pneumolysin in step pneumoniae

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6
Q

What are three strategies used by intracellular pathogens use to resist killing by phagocytes?

A

Inhibit phagosome-lysosome fusion

Survive inside phagolysosomes

Escape from phagosome

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7
Q

How do intracellular bacteria inhibit phagosome-lysosome fusion? What is an example of this?

A

Secrete proteins that block phagosome maturation - type III secretion system in salmonella typhimurium

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8
Q

How do intracellular bacteria survive inside phagolysosomes? What are examples of this?

A

Resist degradation by acidic pH, produce enzumes to counteract ROA and RNI radicals : KatG (catalase) or SodA (superoxide dismutase)

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9
Q

How do intracellular bacteria escape from the phagosome? What is an example of this?

A

Secrete enzyme(s) that degrade phagosomal membrane : LLLO (listeriolysin O) production in Listeria monocytogenes

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10
Q

What are the benefits and costs of being an intracellular pathogen?

A

Benefits: environ nutrient rich, live in protected niche with shelter from immune components and bacterial competition.

Limits: overcoming host barrier, resist immune components, survive in hostile environement (pH, antimicrobials, reactive oxygen/nitrogen species)

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11
Q

What are examples of obligate intracellular pathogens?

A

Chlamydia
Rickettsia spp.
Coxiella burnetii

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12
Q

What are examples of facultative intracellular pathogens (can live in our outside of the cell)?

A 
Mycobacterium tuberculusis 
Salmonella spp. 
Brucella spp.
Legionella pneumophila 
Shigella spp.
Francisella tularensis 
Listeria monocytogenes 
Escherichia coli
Yersinia spp.
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13
Q

What are the functions of macrophages?

A

First line defense-innate immunity.

Derived from peripheral blood monocytes. Leave vasculature and differentiate into tissue macrophages.

Activated upon ingestion of bacteria also activated by cytokines or chemokines.

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14
Q

There are five functional steps of phagocytosis?

A
  1. Recognition
  2. Uptake
  3. Maturation
  4. Killing
  5. Antigen presentatien
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15
Q

What do bacteria recognize on pathogens?

A
  1. Bacterial cell wall or membrane

2. Components of the immune system following opsonization

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16
Q

What type of receptors do macrophages express?

A

PRRs recognize LPS in gram 0 and LTA in gram +

Receptors that recognize plasma-derived molecules, and other signature elements on bacteria.

17
Q

How do extracellular pathogens avoid recognition?

A

Capsules

18
Q

How does bacterial uptake into a cell occur?

A
  1. Ligand-receptor activates cascade signal transduction
  2. Surface structure remodeled by polymerizing and depolymerizing actin
  3. Bacterium is internalized within a membrane bound phagosome (usually passive, although some bacteria influence their own internalization)

Some bacteria use specialized entry mechanisms to avoid normal phagosome maturation.

19
Q

What occurs when a macrophage takes up a bacteria?

A

Passive process.

PM remodels only at site of recognition via PM extensions due to location actin polymerization.

20
Q

What are the three ways by which bacteria can be taken up?

A

General phagocytosis: reminants of membrane rearrange around bacteria to facilitate engulfment (rickettsia)

Looping phagocytosis: arms loop around to engulf the cell (francisella)

Coiling phagocytosis (legionella)

21
Q

What mechanisms can bacteria sue to actively induce their own uptake to enter non-phagocytic cells?

A

Trigger mechanism: major membrane perturbations with remodeling promoted by bacterial effector proteins injected into host cell (salmonella)

Zipper mechanism: minor membrane perturbations with minimal remodeling caused by bacteria sliding into the cell (listeria)

22
Q

Describe the maturation of bacteria-containing phagosomes?

A

Proceeds by fusion with endocytic vesicles.

Depending on proteins present on vesicle surface, it’s either “Early” endosome or “late” endosome.

Last vesicle to fuse with the phagosome is the lysosome which results in generation of the phagolysosome.

23
Q

What is the major difference between the early and late phagosomes and the phagolysosomes?

A

The phagolysosome is the worst environment for organism survival.

Phagolysosome has the most vacuolar ATPases that acidify the environment.

Also has NADPH oxidase and other microbicidal enzymes.

24
Q

What are four ways by which bacteria alter phagosome trafficking?

A
  1. Survive and replicate in the phagolysosome
  2. Make proteins to escape and replicate in the cytosol
  3. Modulate endocytic pathway by blocking maturation and preventing transition from early to late phagosome
  4. Alternative trafficking pathway - legionella, brucella, chlamydia
25
Q

What bacteria can survive and replicate within the phagosome?

A

Coxiella spp.

26
Q

What bacteria can escape the phagosome and replicate in the cytosol?

A

Rikettsia, shigella, E. coli, listeria, francisella.

27
Q

What bacteria modulate the endocytic pathway to prevent phagosome fusing with the lysosome?

A

Salmonella and mycobacterium.

28
Q

What bacteria use alternative trafficking pathways to alter phagosome trafficking?

A

Legionella and brucella.

29
Q

What are oxygen-dependent killing mechanisms that kill bacteria in the lysosome.

A

Generate nitric oxide via intracellular nitric oxide synthase.

NADPH oxidase generates superoxide.

30
Q

What are oxygen-independent killing mechanisms used to kill bacteria in the lysosome.

A

Pumping protons in via vacuolar ATPases to acidify the environment.

Lysozyme and defensins.

31
Q

How are bacterial antigens processed?

A

Antigen degraded into oligopeptides 13-18 aas.

Binds to class 1 or 2 MHC

Antigen presented on surface stimulates T cell response

Dec=graded material exocytosed and can be presented by nearby APC.

32
Q

What effect does bacterial internalization have on mø?

A

activation: induces cytokine production which is beneficial when release in moderation.

Mediates lymphocyte recruitment and cross-activation of other immune cells.

Increases vascular permeability.

33
Q

What are some negative consequences of bacteria ingestion by macrophages?

A

Tissue injury and disease upon continuous stim; chronic inflammation contributes to autoimmune disease.

ROI/RNI, hydrolytic enzymes damage tissue

TNFa and IL-1 fever, wasting, septic shock

Can act as “trojan horse” to disseminate pathogens (monocytes and PMNS, not mø b/c they’re tissue residents)

IAHI Block 2 (16 decks)

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