Microbial Pathogenesis

• Pathogenesis is the manner of development of a disease
• Bacterial pathogenesis is the mechanism by which bacteria cause infectious illness
• Bacteria cause diseases directly by damaging host cells and indirectly by stimulating exaggerated host inflammatory/immune response
• Higher number of pathogens increase the likelihood of developing disease
• LD 50 (50% lethal dose) is the number of bacteria required to kill half (50%) of the host
• ID 50 (50% infectious dose) is the number of bacteria required to cause infection in half (50%) of the host
• Infectious dose varies among pathogenic bacteria
• Virulence factors are molecular components expressed by a pathogen that increase its ability to cause disease
• Bacterial toxins are categorized into exotoxins and endotoxins
• Exotoxins are soluble, heat-labile proteins released into the surrounding as the bacteria grows
• Exotoxins are mostly by Gram positive bacteria and can elicit protective antitoxic antibodies
• Roles of exotoxins in disease include ingestion of preformed toxin, colonization of wound or surface followed by toxin production, and exotoxin produced by bacteria in tissues to aid growth and spread
• Types of exotoxins include A-B toxins (intracellular acting), membrane disrupting (surface damaging), superantigens, and extracellular enzymes
• 1. B toxins (intracellular acting) are composed of two parts: A and B portions
• Examples of A-B toxins (intracellular acting) include Diphtheria toxin, Cholera toxin, Shiga toxin, and Clostridium botulinum
• Membrane disrupting toxins cause damage or disruption of plasma membranes
• Superantigens result in excessive activation of the immune system
• Coagulase triggers the polymerization of fibrin, resulting in cross-linking of bacteria in the clot
• Hyaluronidases break down Hyaluronic acid found in connective tissues
• Extracellular enzymes break down host macromolecules and play an important role in disease development
• Examples of extracellular enzymes include Collagenase, Hemolysins, and Dnase
• Endotoxins are released when cells die and are the component of the outer membrane of gram-negative bacteria
• Endotoxic shock occurs when bacterial products reach high enough levels in the blood to trigger complement activation, cytokine release, and coagulation cascade activation
• Bacterial invasion of host tissues involves facultative intracellular parasites, obligate intracellular parasites, and extracellular parasites
• Steps in bacterial invasion include motility, adherence, invasion of host cells, and manipulation of host cell functions
• Motility involves flagella, corkscrew type, and gliding motility
• Adherence strategies include fimbriae and monomeric protein adhesins
• Invasion of host cells by bacteria can occur through zippering or triggering mechanisms
• Following attachment to host cells, pathogens cause changes in host cell cytoskeleton that cause the pathogen to be internalized
• Some pathogens can utilize actin fibers intracellularly to move through host cells
• Invasins may mediate uptake of bacteria into professional phagocytic cells in a way that bypasses normal phagosome formation
• Bacterial pathogens can manipulate host cell functions
• Listeria monocytogenes:

  • Produce exotoxin and virulence factors (listeriolysin O, phospholipase A, B, and C) to destroy the phagolysosome's membrane and escape
  • Multiply in the host cell's cytoplasm and use actin filaments as a tail to move towards the membrane
  • Exit the cell using pseudopods
  • Enter neighboring cells forming a double membrane vacuole that the pathogen needs to escape from
  • Spread from cell to cell, hiding from the immune system
• Pathogenic bacteria obtain essential nutrients through:

  • Obligate intracellular bacteria parasitize living cells for an extended period
  • Extracellular pathogens often lyse cells to obtain nutrients
  • Intracellular pathogens escape phagosomes to enter nutrient-rich cytoplasm or modify vacuoles to get nutrients
• Bacterial strategies for obtaining iron:

  1. Siderophores chelate iron with high affinity

  2. Direct binding of host iron-containing proteins by bacterial surface receptors

  3. Exotoxins that lyse host cells
• Immune evasion strategies of pathogens:

  • Cell wall modification: altering lipid A component to repel host antimicrobial peptides
  • Capsule production: Neisseria meningitidis uses a polysaccharide capsule to hide from the immune system
  • Mimicry: bacteria reduce the negative charge of cell wall teichoic acids to evade immune responses
• Bacterial Sabotage via Effector Proteins:

  • Staphylococcus aureus inhibits immune responses with effector proteins like staphylococcal protein A
  • Mycobacterium tuberculosis inhibits phagosomal acidification using tyrosine phosphatase PtpA
• Evasion of host immune response:

  • Serum resistance prevents bacterial lysis by the membrane attack complex
  • Capsules mediate resistance to complement
  • Bacteria resist opsonization/phagocytosis through various mechanisms
• Strategies for surviving phagocytosis:

  • Escape from phagosome before fusion with lysosome
  • Prevent phagosome-lysosome fusion using type 3 secretion system
  • Express factors for survival in harsh phagolysosome conditions
• Evading antibodies:

  • Ig proteases
  • Antigenic switching or phase variation
  • Masking with sialic acid, hyaluronic acid, or host proteins like fibronectin