Microbial Pathogenesis

• Pathogenesis is the manner of development of a disease
• Bacterial pathogenesis is the mechanism by which bacteria cause infectious illness
• Bacteria can cause diseases directly by damaging host cells or indirectly by stimulating an exaggerated host inflammatory/immune response
• The number of invading microbes affects the likelihood of developing a disease
• LD50 (50% lethal dose) is the number of bacteria required to kill half of the host, while ID50 (50% infectious dose) is the number of bacteria required to cause infection in half of the host
• Virulence factors are molecular components expressed by a pathogen that increase its ability to cause disease. They cause damage to the host or promote colonization and survival of the bacteria
• Bacterial toxins can be exotoxins or endotoxins
• Exotoxins are soluble, heat-labile proteins released by gram positive bacteria into the surrounding environment. They travel from the site of infection to other body tissues or target cells to exert their effects
• Exotoxins can elicit protectice antitoxic antibodies or be converted to nontoxic immunizing agents termed toxoids. They are antigenic as well.
• Roles of exotoxins in disease include ingestion of preformed toxin, colonization of wounds, and aiding growth and spread of bacteria in tissues
• Types of exotoxins include A-B toxins (intracellular acting) and membrane disrupting toxins
• 1. B toxins (intracellular acting) have subunits A and B, where A acts as an enzyme and B binds with the membrane receptor of the target cell
• Examples of A-B toxins include Diphtheria toxin, Cholera toxin, Shiga toxin, and Clostridium botulinum toxin
• Membrane disrupting toxins cause damage or disruption of plasma membranes, leading to osmotic lysis and cell death
• Superantigens are toxins that result in excessive activation of the immune system
• Coagulase triggers the polymerization of fibrin, allowing bacteria to escape from the host immune system
• Hyaluronidases break down Hyaluronic acid, aiding in the spread of bacteria by degrading extracellular matrix
• Extracellular enzymes break down host macromolecules, providing nutrients or aiding in dissemination
• 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 trigger complement activation, cytokine release, and coagulation cascade activation in the body, leading to circulatory system collapse and multiple organ system failure
• Host damage during invasion can be caused by direct disruption of function or an exaggerated immune response that compromises tissue
• Host damage during bacterial invasion can be caused by direct disruption of function or an exaggerated immune response that compromises tissue function
• Invasive bacteria are classified as:

  • Facultative Intracellular Parasites:
  • Not confined to cells
  • Some can multiply in professional phagocytic cells
  • Some bacteria may survive in an intracellular state for months or years (e.g., Mycobacterium)
  • Obligate Intracellular Parasites:
  • Can only propagate inside host cells
  • Examples include chlamydia and rickettsia
  • Extracellular parasites:
  • Cause tissue damage outside phagocytes and other cells
  • Do not have the ability to survive long periods in cells
  • Example: vibrio cholerae
• Steps in bacterial invasion:

  • Motility:
  • Flagella are adapted for low viscosity fluids
  • Other types of motility include corkscrew type (best in viscous solutions) and gliding motility (movement over solid surfaces)
  • Chemotaxis is directional swimming using a gradient, especially nutrients
• Adherence:

  Two common strategies are fimbriae and monomeric protein adhesins.

  1. Fimbriae and pili:

  • Receptors are usually carbohydrate residues of glycoproteins or glycolipids
  • Attachment is more fragile
  • Highly specific binding, often mediated by adhesins, can be blocked by antibodies specific for host tissue type/location

  2. Monomeric protein adhesins:

  • Mediated by cell surface proteins
  • Tighter binding to host cell
  • May recognize proteins on host cell surface
  • May follow looser fimbrial attachment
• Invasion of host cells (intracellular pathogens):

  • Some invasive bacteria have mechanisms for entering host cells that are not naturally phagocytic
  • Two types of bacterial-mediated invasion:

  a. Zippering:

  • Bacteria present ligands on their surface to bind to host cells and initiate the entry process

  b. Triggering:

  • Bacteria inject effectors into host cells via T3 SS to regulate phagocytosis (e.g., Salmonella)
• Specialized secretion systems inject effector proteins directly into the host cell cytoplasm
• Following attachment to host cells, pathogens cause changes in host cell cytoskeleton (actin) that cause the pathogen to be internalized

  • Some pathogens can utilize actin fibers intracellularly to move through host cells (transcytosis)
  • Invasions may also mediate uptake of bacteria into professional phagocytic cells bypassing normal phagosome formation
• Bacterial pathogens manipulate host cell functions to perform functions favorable to the pathogen

  • Listeria monocytogenes:
  • Produce exotoxins and virulence factors to destroy the phagolysosome's membrane and escape
  • Multiply in the cytoplasm of the host's cell and use actin as a tail to move
  • Exit from the cell using pseudopods
  • Spread from cell to cell, hiding from the immune system
• Pathogenic bacteria have intricate methods to obtain essential nutrients

  • Obligate intracellular bacteria parasitize the living cell for an extended period
  • Host cytoplasm is a nutrient-rich environment
  • Iron:
  • Host tissues are low in iron because it is bound to transferrin, lactoferrin, ferritin, and heme.
  • Bacterial strategies for obtaining iron include siderophores, direct binding of host iron-binding proteins, and exotoxins that lyse host cells
• Immune evasion strategies of pathogens:

  • Cell Wall Modification
  • Capsule Production
  • Mimicry

  The cell wall:

  • First target of the human immune system
  • uses tools such as antibodies and antimicrobial peptides (AMPs) to kill and neutralize the bacteria.
  • Modulation of the outermost layer is an evasive technique used widely across bacterial species
• Capsule Production:

  • Neisseria meningitidis:
  • Polysaccharide capsule helps protect the bacteria from the immune system
  • Contributes to the success of N. meningitidis as a pathogen
• Bacterial evasion of host immune response:

  • Capsule helps protect bacteria by hiding it from the immune system
  • Genes for capsule synthesis are downregulated during early infection for invasion of host cell
  • Bacteria produce capsule again upon entering the bloodstream to survive in the presence of immune factors
  • Capsular polysaccharide provides protection against antimicrobial peptides found inside host cells
• Neisseria meningitidis:

  • Inhibits host immunity with effector proteins
  • Capsular polysaccharide provides protection against AMPs
  • Directly blocks host immunity with effector proteins
• S. aureus:

  • Infections are common due to poor adaptive immune responses
  • Effector proteins like staphylococcal protein A (SpA) inhibit effective immune responses
  • SpA binds directly to antibodies to prevent recognition and killing of S. aureus
  • SpA binds to B-cell receptors, inactivating cells generating a protective immune response
• M. tuberculosis (Mtb):

  • Causes active tuberculosis disease in some, but most experience latent infection
  • Mtb can lie dormant in host's lungs for decades
  • Mtb inhibits phagosomal acidification with tyrosine phosphatase, PtpA
  • PtpA inactivates host vacuolar ATPase, creating a niche for Mtb to persist
• Evasion of host immune response:

  • Serum resistance prevents bacterial lysis by MAC
  • Capsule mediates resistance to complement by preventing C3b binding and promoting C3bH complex formation
  • LPS O polysaccharide can prevent opsonization if it has sialic acid
  • Capsule prevents C3b-mediated opsonization and antibody-mediated opsonization
• Strategies for surviving phagocytosis:

  • Escape from phagosome before fusion with lysosome
  • Prevent phagosome-lysosome fusion
  • Express factors for survival in harsh phagolysosome conditions
• Evading antibody:

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