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Lecture 6 - Phagocytosis
Author: Amelia Virostko

1. Introduction

  1. Phagocytosis: series of receptor-ligand interactions between substrate and phagocyte

2. Definition of phagocytes and their role in protection

  1. Neutrophils: mediators of acute inflammation
  2. Macrophages and monocytes: responsible for chronic inflammation
  3. Eosinophils: clear large parasites and participate in allergic response
  4. Basophils: participate in allergic response
  5. Dendritic cells: antigen presenting cells

3. Bacterial uptake

  1. Phagocyte ingests microorganism by circumferential movement into nascent phagosome
  2. Primary and secondary granules fuse with phagosome to form phagolysosome

4. Phagocyte Receptors

  1. Phagocytic receptors
    1. Integrin family
      1. CR3 binds alternative complement component C3bi
      2. LFA1 binds inflamed endothelium receptor ICAM-1
      3. p150/95 binds polysaccharides
    2. Lectins - pattern recognition receptors
      1. Mannose receptor initiates Mannose Binding Ligand complement pathway
    3. Fc receptors bind IgG-coat
  2. Adhesion receptors
    1. Selectins and integrins
    2. Involved in antigen presentation and chemotactic phagocytic response
  3. Activation receptors
    1. Increase macrophage response to microbial and host components
    2. CR1 binds C3b
    3. IFN* receptor
    4. Toll-like receptor (TLR): recognize direct microbial component
    5. MHC class I or II

5. Opsonization

  1. Lectins, integrins, and complement receptors

6. Complement Role in Phagocytosis

  1. C5-C9 involved in bacterial lysis
  2. C5a chemotactic factor for phagocytes
  3. C3b opsonizes bacteria
  4. C6-C8 deficiency leads to Neisseria bacteremia
  5. C3 deficiency causes severe recurrent pyogenic sinus and respiratory infections

7. Role of Bacterial LPS in Phagocytosis

  1. Recognized by multiple phagocyte receptors
  2. Lipid A: endotoxin portion of LPS recognized by activation receptors
  3. Core oligosaccharide: recognized by lectins
  4. O-antigen: prevents complement deposition and lectin from binding to core oligosaccharide
  5. LPS activation facilitated by TLR-4

8. Neutrophil Migration Through Endothelium

  1. Inflammation leads to selectin production on neutrophils and endothelium
  2. Neutrophils roll on selectin-carbohydrate interactions along endothelium
  3. Selectins responsible for rolling, integrins for adhesion and transmigration
  4. LFA-1 on neutrophils binds ICAM-1 initiating migration

9. Oxidate Burst

  1. Need adhesion with microbe so that radicals are not toxic to host
  2. Mediated by secondary granules
  3. NADPH oxidase reduces molecular oxygen to superoxide, which is converted to toxic radical species
    1. Chronic granulomatous Disease (CGD) occurs due to NADPH oxidase mutations making the host vulnerable to infection by catalase-positive organisms
  4. Occurs before engulfment

10. Oxygen-Indepent Killing

  1. Occurs after engulfment
  2. Primary and secondary granules fuse with phagosome to form phagolysosome
  3. Cationic protein, defensins, and lactoferrin are important for killing microorganisms

11. Bacterial Strategies Against Phagocyte

  1. Cytotoxicity
    1. Streotococci produce Streptolyisn O to kill phagocytes
  2. Inhibit opsonization
    1. Capsule
    2. M protein prevents complement deposition on microbe surface
    3. Pili
  3. Survival inside host cells
    1. Inhibit phagosome-lysosome fusion
    2. Escape from phagosome
    3. Resist lysosomal enzymes
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