Microbial Pathogenesis Overview

Microbial Pathogenesis

• Major "tools" microbes use to cause disease: Microbial pathogens use various attachment mechanisms, avoid the immune system, and damage host cells through toxins and effector proteins.
• Pathogen Entry & Colonization: The first step of infection is attachment, achieved through pili adhesins and non-pili adhesins. Pili are hairlike appendages with adhesion proteins at the tip.
• Biofilms: Biofilms provide a protective layer for pathogens, making them harder to kill.
• Type I pili: Static, hairlike appendages used for attachment
• Type IV pili: Dynamic, thin, and flexible pili used for "twitching motility."
• Colonization: The process of establishing a presence and multiplying in the host
• Nonpilus Adhesions: Cell wall-associated proteins, like pertactin, protein F, and protein M, bind to host proteins for more intimate attachment
• Surviving within a Host: Pathogens distinguish between extracellular and intracellular environments, and display different strategies to survive and avoid the immune system.
• Extracellular Pathogens: Exist outside of host cells. They avoid the immune system by forming capsules, producing proteins that bind to antibodies, and changing surface antigens.
• Intracellular Pathogens: Live inside host cells to avoid the immune system.
  • Facultative Intracellular Pathogens: Can invade host cells but also survive outside. Examples: Salmonella, Shigella, Listera
  • Obligate Intracellular Pathogens: Can only survive and reproduce inside a host cell. Examples: Rickettsia, Coxiella, Bartonella
• Host Damage and Manipulation: Pathogens damage host cells by targeting components of the cell, disrupting signaling pathways, interfering with protein synthesis, and disrupting the cellular membrane.
• Extracellular Immune Avoidance:
  • Capsules: Coat bacterial cell walls to prevent phagocytes from binding.
  • Cell Surface Proteins: Sequester antibodies, like protein A in S. aureus.
  • Antigenic Variation: Vary surface antigens to avoid immune detection.
  • Quorum Sensing: Use cell-to-cell communication to evade the immune system.
• Intracellular Immune Avoidance:
  • Phagosome Escape: Escape the phagosome to avoid destruction by the immune system
  • Phagosome Modification: Modify the phagosome to create a suitable environment for survival
  • Inhibition of Phago-lysosome Fusion: Prevent phago-lysosome fusion to avoid degradation by lysosomes

Exotoxin Modes of Action

• Exotoxins: Proteins produced by bacteria that can damage host cells.
• Cellular Targets of Bacterial Toxins: Pores, actin polymerization, second messenger signaling, the cytoskeleton, vesicular trafficking, cell-cell adhesion, protein synthesis, nucleic acid synthesis, and cell wall synthesis.
• Staphylococcal Alpha Toxin: Forms a seven-membered transmembrane pore in target cell membranes, causing cell lysis.
• Cholera Toxin: An AB toxin that disrupts signal transduction by associating with the G protein and increasing cAMP, leading to diarrhea.
• Diphtheria Toxin: An AB toxin that disrupts protein synthesis by interfering with elongation factor 2, leading to cell death.
• Shiga Toxin: An AB toxin that inhibits protein synthesis by blocking the translation of ribosomes, leading to cell death.
• Anthrax Toxin: A tripartite toxin complex consisting of protective antigen (PA), edema factor (EF), and lethal factor (LF). PA binds to host cell receptors, allowing EF and LF to enter the cell and exert their effects.
  • EF: Causes fluid accumulation in the tissues.
  • LF: Disrupts cellular signaling, leading to cell death
• Endotoxins: Lipopolysaccharide (LPS) found in the outer membrane of Gram-negative bacteria. Can cause fever, inflammation, and shock.