Lecture 02: The innate immune system [MCQ 1]

Innate Immune System: Phagocytosis

• Phagocytes: Macrophages (resident in tissues) and neutrophils (recruited from blood) are crucial for phagocytosis.

• Steps in Phagocytosis:

  • Chemotaxis: Phagocytes are attracted to the site of infection.
  • Attachment: Receptors on the phagocyte bind to pathogen-associated molecular patterns (PAMPs) on the microbe's surface.
  • Ingestion and Phagosome Formation: The phagocyte engulfs the microbe, forming a phagosome.
  • Lysosome Fusion: The phagosome fuses with lysosomes, forming a phagolysosome.
  • Microbial Killing and Digestion: Enzymes, ROS, and the acidic environment in the phagolysosome kill and break down the microbe.
  • Release of Waste: Undigested material is released.

Recognizing Microbes

• PAMPs and PRRs: Pathogen-associated molecular patterns (PAMPs) on microbes are recognized by pattern recognition receptors (PRRs) on phagocytes.

• Macrophage PRRs (e.g., Toll-like receptors): Macrophages possess various TLRs, each recognizing specific microbial components.

  • TLR2: Recognizes peptidoglycan (bacterial cell wall).
  • TLR4: Recognizes lipopolysaccharide (LPS; bacterial cell wall).
  • TLR5: Recognizes flagellin (bacterial flagella).
  • TLR7: Recognizes ssRNA (viruses like influenza and HIV-2).
  • TLR9: Recognizes dsDNA (bacteria and herpes viruses).
  • TLR10: Recognizes flagellin (bacterial flagella). There are 13 different types of TLRs in total.

• Types of PAMPS: - Nucleic acids: Double-stranded RNA (dsRNA) and single-stranded RNA (ssRNA) found in viruses. - Proteins: Flagellin (bacterial flagella), pilin (bacterial pili). - Lipids: Lipopolysaccharide (LPS) in Gram-negative cell walls, and lipoteichoic acid in Gram-positive cell walls. - Carbohydrates: Mannan (fungi and bacteria), glucans (fungi), peptidoglycan (bacteria).

Opsonization:

• Opsonization is a process where pathogens are coated with opsonins (like antibodies or complement proteins).
• This enhances phagocyte binding and phagocytosis.
• Steps:
  • Tagging: Antibodies coat the pathogen.
  • Recognition: Macrophages recognize the antibody's Fc region using their Fc receptors.
  • Engulfing: The macrophage binds to the antibody and engulfs the pathogen.
  • Killing: The pathogen is destroyed within the phagolysosome.

Phagosome Maturation

• Phagosome Formation: The microbe is engulfed.

• Phagosome-Endosome Interactions: The phagosome interacts with early endosomes, which contribute proteins to initiate maturation.

• Phagosome-Late Endosome Interactions:The maturing phagosome fuses with late endosomes. This step creates an increasingly acidic environment.

• Phagosome-Lysosome Fusion: The phagosome fuses with a lysosome, creating a phagolysosome.

Microbial Killing and Digestion

• Phagolysosome environment: The phagolysosome contains hydrolytic enzymes (proteases, lipases), ROS, and an acidic environment (pH 3.5-4) to kill and digest the pathogen.

Debris Clearance

• Waste Disposal: Indigested material is either released as waste or processed to present antigens, triggering adaptive immunity.

Mechanisms of Microbial Killing

• Acidification: Decreasing the pH (3.5-4) via H+ ATPase pumps.
• Reactive Oxygen Species (ROS): e.g., hypochlorite(OCL-), nitric oxide, superoxide, peroxynitrite.
• Antimicrobial Peptides (AMPS): Defensins create ion pores in the microbial membrane.
• Enzymes: Lysozymes degrade peptidoglycan in Gram-positive bacteria. Ribonucleases (RNases), DNases, and proteases degrade other components.
• Nutrient Depletion: Siderophores and nutritional transport systems deprive microbes of essential nutrients.

Cellular Signaling and Immune Gene Expression

• TLR Signal Transduction: Binding of PAMPs to TLRs initiates signaling pathways, leading to the expression of immune genes.
• Transcription Factors: The key transcription factor NF-κB is activated.
• Cytokines: Production of cytokines is induced, recruiting and activating other immune cells.
• AMPS and Inflammatory Mediators: Mediators that amplify the inflammatory response are up-regulated.
• Phagosomal Proteins: Proteins involved in phagosome maturation and microbial degradation are enhanced.