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Exotoxin Overview
  • Exotoxins are proteins released by both Gram-positive and Gram-negative bacteria
    • certain Gram-positive and Gram-negative bacteria produce exotoxins
    • exotoxins are not heat stable
      • destroyed rapidly at 60°C
        • except Staphylococcal enterotoxin
  • Exotoxin types and examples of each
    • enterotoxins
      • act on the GI tract to cause diarrhea
      • cause osmotic pull of fluid into the intestines
      • 2 mechanisms by which enterotoxins cause disease
        • infectious diarrhea
          • bacteria colonize GI tract and continuously secrete enterotoxin
          • diarrhea continues until infection is cleared
          • examples
            • Vibrio cholera
            • E. coli
            • Campylobacter jejuni
            • Shigella dysenteriae
        • food poisoning 
          • bacteria grow in food and release enterotoxin into food
          • less than 24 hours of diarrhea and vomiting
          • examples
            • Bacillus cereus
            • Staphylococcus aureus
    • neurotoxins
      • act on the nerves or NMJ to cause paralysis
      • Clostridium tetani
    • pyrogenic exotoxins
      • stimulate release of cytokines
      • cause rash, fever, toxic shock syndrome
      • S. aureus, Streptococcus pyogenes
    • tissue invasive exotoxins
      • enzymes that destroy tissue to allow bacteria to invade the host
      • "SHiN" bacteria
      • group A streptococcus
  • cAMP inducers
    • V. cholerae, Bordetella pertussis, and E. coli (ETEC)
      • via ADP ribosylation
    • Bacillus anthracis 
      • edema factor is an adenylate cyclase
  • A-B ADP ribosylation
    • Corynebacterium diphtheriae and Pseudomonas
    • Vibrio cholerae
    • E. coli
    • Bordetella pertussis
  • S. aureus secretes multiple types of exotoxins as described below
    • superantigen TSST-1
    • enterotoxin
    • exfoliatin
    • protein A
Enterotoxins
  • V. cholerae toxin
    • AB toxin
      • A subunit is active
    • ADP ribosylation of G protein stimulates adenylyl cyclase
      • permanently activates Gs
    • ↑ pumping of Cl- into gut and ↓ Na+ absorption
    • H2O moves into gut lumen
    • causes voluminous rice-water diarrhea
    • "turns the 'on' on"
  • E. coli (ETEC) 
    • heat-labile toxin stimulates adenylate cyclase → ↑ cAMP
      • increase Cl- secretion and H2O efflux
      • just like cholera
    • heat-stable toxin stimulates guanylate cyclase → ↑ cGMP
      • decrease resorption of NaCl and H2O
    • both cause watery diarrhea
    • "Labile like the Air, stable like the Ground"
Neurotoxins
  • C. tetani
    • blocks the release of inhibitory neurotransmitters GABA and glycine
    • causes "lockjaw"
    • zinc-dependent protease
  • C. botulinum
    • blocks the presynaptic release of acetylcholine at the NMJ
    • causes anticholinergic symptoms, CNS paralysis (especially cranial nerves)
    • spores found in honey (causes floppy baby)
    • improperly canned food contains preformed toxin (effects adults)
    • zinc-dependent protease
Pyrogenic exotoxins
  • S. aureus
    • TSST-1 superantigen causes toxic shock syndrome (fever, rash, shock)
      • binds directly to MHC II and T cell receptor simultaneously, activating large numbers of T cells to stimulate release of IFN-γ, IL-2, IL-1
    • additionally, S. aureus secretes
      • enterotoxins
        • cause food poisoning
      • exfoliatin
        • causes staphylococcal scalded skin syndrome
      • protein A
        • binds Fc region of Ig
        • prevents opsonization and phagocytosis
  • S. pyogenes
    • scarlet fever-erythrogenic toxin causes toxic shock-like syndrome
    • streptolysin O is a hemolysin
    • antigen for ASO antibody
      • used in the diagnosis of rheumatic fever
Tissue invasive exotoxins
  • S. pneumoniae, Haemophilus influenza type B, and Neisseria
    • all secrete IgA protease in order to colonize respiratory mucosa
      • enzyme that cleaves IgA
    • recall that these 3 bacteria are the "SHiN" encapsulated bacteria
  • Group A streptococcus
    • M protein
      • helps prevent phagocytosis
Miscellaneous exotoxins
  • Shiga toxin
    • inactivates mammalian 60S ribosomal subunit
      • prevents binding of tRNA to 60S subunit
    • Shiga toxin released by Shigella
    • Shiga-like toxin (similar mechanism) released by EHEC
      • active A subunit + 5 binding B subunits
      • plasmid transmitted to E. coli by temperate bacteriophage
  • B. pertussis
    • AB toxin
    • increases cAMP by inhibiting Gαi
    • causes whooping cough
    • "turns the 'off' off"
    • inhibits chemokine receptor, causing lymphocytosis
    • impairs phagocytosis by host
  • B. anthracis toxin
    • induces edema factor, a bacterial adenylate cyclase (↑ cAMP)
  • Corynebacterium diphtheriae
    • AB toxin
      • B subunit binds cardiac and neural cells
    • A subunit inactivates elongation factor 2 (EF-2) → inhibit host cell protein synthesis → death
      • via ADP ribosylation
      • EF-2 is needed for peptide chain translocation on the ribosome during translation
      • also seen with Pseudomonas exotoxin A
    • causes pharyngitis and "pseudomembrane" in throat
  • C. difficile
    • A-B cytotoxin kills enterocytes and causes pseudomembranous colitis
      • toxin A
        • attracts neutrophils, causing inflammation
        • causes loss of water into gut lumen
      • toxin B
        • actin depolymerization
        • loss of cytoskeleton integrity
  • C. perfringens
    • α toxin (also known as phospholipase C or lecithinase) causes gas gangrene
      • get double zone of hemolysis on blood agar
      • degrades lecithin, a component of cell phospholipid membranes
      • causes loss of cell membrane integrity
      • leads to membrane destruction, cell death, necrosis, hemolysis
 

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