Lecture 02: The innate immune system [MCQ 2]

Innate Immune System: Phagocytosis

• Phagocytes: Macrophages (resident tissues) and neutrophils (recruited from blood) carry out phagocytosis.

• Steps of Phagocytosis:

  • Chemotaxis: Phagocytes are drawn to the site of infection.
  • Attachment: Receptors on phagocytes bind to pathogen-associated molecular patterns (PAMPs).
  • Ingestion: The pathogen is engulfed, forming a phagosome.
  • Lysosome fusion: The phagosome fuses with a lysosome forming a phagolysosome.
  • Microbial killing and digestion: Enzymes and reactive oxygen species (ROS) break down the pathogen.
  • Waste release: Undigested material is expelled.

Recognizing Microbes

• Pattern Recognition Receptors (PRRs): Phagocytes use PRRs to detect pathogens.

  • Toll-like receptors (TLRs): A family of PRRs, crucial for pathogen recognition.
    • TLR2: Recognizes peptidoglycan (bacterial cell wall component).
    • TLR4: Recognizes lipopolysaccharide (LPS) (bacterial cell wall component).
    • TLR5: Recognizes flagellin (bacterial appendage).
    • TLR7: Recognizes single-stranded RNA (ssRNA) (viral).
    • TLR9: Recognizes double-stranded DNA (dsDNA) (viral and bacterial).
    • TLR10: Recognizes flagellin

• Pathogen-Associated Molecular Patterns (PAMPs): Pathogen features that are recognized by PRRs. These are largely conserved molecular structures on pathogens, which are not easily mutated.

  • Types: Nucleic acids (like viral ssRNA and dsRNA), proteins (flagellin, pilin), lipids (LPS, lipoteichoic acid), and carbohydrates (mannan, glucans, peptidoglycan).

Opsonization

• Process: Coating pathogens with opsonins (like antibodies or complement proteins) enhances their recognition and uptake by phagocytes. This significantly boosts phagocytosis efficiency.

• Steps:

  • Tagging: Antibodies coat the pathogen.
  • Recognition: Macrophages recognize the Antibody's Fc region.
  • Engulfing: The macrophage binds to the tagged pathogen, and engulfs it.
  • Killing: The pathogen is destroyed within the phagocyte.

Phagosome Maturation

• Phagosome formation: Pathogen is enveloped within the phagosome.
• Fusion with Early Endosomes: The phagosome interacts with early endosomes to receive proteins involved in maturation.
• Fusion with Late Endosomes: The phagosome fuses with late endosomes, and the environment acidifies.
• Fusion with Lysosomes: The phagosome fuses with lysosomes forming the phagolysosome, which is crucial for digestion.

Microbial Killing and Digestion

• Phagolysosome Content: The phagolysosome contains enzymes (e.g., proteases, lipases), ROS, and a low pH that kills and breaks down pathogens.

Debris Clearance

• Waste Disposal: Indigestible material is expelled or used for antigen presentation.

Macrophage Killing Mechanisms

• Acidification: Reducing pH (3.5-4) using H+ ATPase pumps kills some microbes.
• Reactive Oxygen Species (ROS): Hypochlorite, nitric oxide, superoxide radical kill pathogens.
• Antimicrobial Peptides (AMPs): Defensins create pores in pathogen membranes.
• Enzymes: Lysozyme degrades peptidoglycans in bacterial cell walls.
• Nutrient Removal: Macrophages remove nutrients used by pathogens.

Cell Signalling and Immune Gene Expression

• TLR activation: TLRs signal intracellularly, triggering immune gene expression.
• NF-κB: A key transcription factor activated by TLRs. This factor activates the production of inflammatory proteins, cytokines, and antimicrobial peptides (AMPS).
• Cytokines: Molecules that amplify inflammatory responses and activate other immune cells.
• Inflammatory proteins: Amplified through NF-κB activation, further enhancing inflammatory responses.
• Phagosomal proteins: enhance the ability of macrophages to kill pathogens by regulating phagosome maturation and degradation.