Exotoxins

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 G_s
  • ↑ 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 Gα_i
  • 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