Updated: 6/9/2018

Exotoxins

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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 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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Questions (5)
Lab Values
Blood, Plasma, Serum Reference Range
ALT 8-20 U/L
Amylase, serum 25-125 U/L
AST 8-20 U/L
Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca2+) 8.4-10.2 mg/dL
Cholesterol, serum Rec: < 200 mg/dL
Cortisol, serum 0800 h: 5-23 μg/dL //1600 h:
3-15 μg/dL
2000 h: ≤ 50% of 0800 h
Creatine kinase, serum Male: 25-90 U/L
Female: 10-70 U/L
Creatinine, serum 0.6-1.2 mg/dL
Electrolytes, serum  
Sodium (Na+) 136-145 mEq/L
Chloride (Cl-) 95-105 mEq/L
Potassium (K+) 3.5-5.0 mEq/L
Bicarbonate (HCO3-) 22-28 mEq/L
Magnesium (Mg2+) 1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)  
24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL
Ferritin, serum Male: 15-200 ng/mL
Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL
Female: premenopause: 4-30 mIU/mL
midcycle peak: 10-90 mIU/mL
postmenopause: 40-250
pH 7.35-7.45
PCO2 33-45 mmHg
PO2 75-105 mmHg
Glucose, serum Fasting: 70-110 mg/dL
2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation Fasting: <5 ng/mL
Provocative stimuli: > 7ng/mL
Immunoglobulins, serum  
IgA 76-390 mg/dL
IgE 0-380 IU/mL
IgG 650-1500 mg/dL
IgM 40-345 mg/dL
Iron 50-170 μg/dL
Lactate dehydrogenase, serum 45-90 U/L
Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL
Female: follicular phase: 5-30 mIU/mL
midcycle: 75-150 mIU/mL
postmenopause 30-200 mIU/mL
Osmolality, serum 275-295 mOsmol/kd H2O
Parathyroid hormone, serume, N-terminal 230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L
Phosphorus (inorganic), serum 3.0-4.5 mg/dL
Prolactin, serum (hPRL) < 20 ng/mL
Proteins, serum  
Total (recumbent) 6.0-7.8 g/dL
Albumin 3.5-5.5 g/dL
Globulin 2.3-3.5 g/dL
Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL
Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h
Thyroxine (T4), serum 5-12 μg/dL
Triglycerides, serum 35-160 mg/dL
Triiodothyronine (T3), serum (RIA) 115-190 ng/dL
Triiodothyronine (T3) resin uptake 25%-35%
Urea nitrogen, serum 7-18 mg/dL
Uric acid, serum 3.0-8.2 mg/dL
Hematologic Reference Range
Bleeding time 2-7 minutes
Erythrocyte count Male: 4.3-5.9 million/mm3
Female: 3.5-5.5 million mm3
Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/h
Female: 0-20 mm/h
Hematocrit Male: 41%-53%
Female: 36%-46%
Hemoglobin A1c ≤ 6 %
Hemoglobin, blood Male: 13.5-17.5 g/dL
Female: 12.0-16.0 g/dL
Hemoglobin, plasma 1-4 mg/dL
Leukocyte count and differential  
Leukocyte count 4,500-11,000/mm3
Segmented neutrophils 54%-62%
Bands 3%-5%
Eosinophils 1%-3%
Basophils 0%-0.75%
Lymphocytes 25%-33%
Monocytes 3%-7%
Mean corpuscular hemoglobin 25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration 31%-36% Hb/cell
Mean corpuscular volume 80-100 μm3
Partial thromboplastin time (activated) 25-40 seconds
Platelet count 150,000-400,000/mm3
Prothrombin time 11-15 seconds
Reticulocyte count 0.5%-1.5% of red cells
Thrombin time < 2 seconds deviation from control
Volume  
Plasma Male: 25-43 mL/kg
Female: 28-45 mL/kg
Red cell Male: 20-36 mL/kg
Female: 19-31 mL/kg
Cerebrospinal Fluid Reference Range
Cell count 0-5/mm3
Chloride 118-132 mEq/L
Gamma globulin 3%-12% total proteins
Glucose 40-70 mg/dL
Pressure 70-180 mm H2O
Proteins, total < 40 mg/dL
Sweat Reference Range
Chloride 0-35 mmol/L
Urine  
Calcium 100-300 mg/24 h
Chloride Varies with intake
Creatinine clearance Male: 97-137 mL/min
Female: 88-128 mL/min
Estriol, total (in pregnancy)  
30 wks 6-18 mg/24 h
35 wks 9-28 mg/24 h
40 wks 13-42 mg/24 h
17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 h
Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total Male: 8-20 mg/24 h
Female: 6-15 mg/24 h
Osmolality 50-1400 mOsmol/kg H2O
Oxalate 8-40 μg/mL
Potassium Varies with diet
Proteins, total < 150 mg/24 h
Sodium Varies with diet
Uric acid Varies with diet
Body Mass Index (BMI) Adult: 19-25 kg/m2
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(M1.MC.75) A 19-year-old man returns from travel in South America. He presents complaining of profuse, watery diarrhea. You suspect the causative organism to be Enterotoxigenic E. coli. What is the mechanism by which this organism causes diarrhea? Review Topic

QID: 106707
1

Blocks the release of inhibitory neurotransmitters GABA and glycine

2%

(3/192)

2

Blocks the presynaptic release of acetylcholine at the neuromuscular junction

1%

(1/192)

3

Inactivates mammalian 60S ribosomal subunit

19%

(36/192)

4

Stimulates release of cytokines

2%

(3/192)

5

Stimulates adenylate cyclase (increasing cAMP)

77%

(147/192)

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(M1.MC.75) A 22-year-old woman comes to the urgent care clinic with sudden onset of severe vomiting. She had been at a picnic with her boyfriend a few hours earlier, enjoying barbecue, potato salad, and cake. Shortly thereafter, she began vomiting and has vomited 5 times in the last 3 hours. She has no prior history of symptoms. After a few hours of observation, her symptoms abate, and she is safely discharged home. Which of the following is the most likely cause of her vomiting? Review Topic

QID: 106732
1

Viral infection

0%

(0/11)

2

Hepatitis

0%

(0/11)

3

Gallstones

0%

(0/11)

4

Toxin ingestion from spore-forming organism

36%

(4/11)

5

Toxin ingestion from non-spore-forming organism

64%

(7/11)

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