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Updated: Jun 19 2020

Exotoxins

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  • Exotoxin Overview
    • Exotoxins are proteinsreleased 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 from Renshaw cells in the spinal cord
      • causes opisthotonus, trismus (lockjaw), and risus sardonicus
      • 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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