How virulence is tested on Step 1
Questions name a toxin effect (watery diarrhea, spastic paralysis, flaccid paralysis, diffuse rash with shock) and ask for the molecular mechanism or the organism, or describe a patient with recurrent infections by encapsulated bacteria and ask for the immune defect.
Adhere (pili, fimbriae), evade (capsule, protein A, IgA protease, antigenic variation), invade (invasins, intracellular survival), and damage (exotoxins, endotoxin, enzymes).
Surface and immune-evasion factors
These factors let bacteria colonize and survive long enough to cause disease.
| Encapsulated organism | Clinical note |
|---|---|
| Streptococcus pneumoniae | Pneumonia, meningitis, otitis; overwhelming sepsis after splenectomy |
| Haemophilus influenzae type b | Epiglottitis, meningitis; Hib conjugate vaccine |
| Neisseria meningitidis | Meningococcemia; conjugate vaccine |
| Klebsiella pneumoniae | Mucoid colonies; aspiration pneumonia |
| Salmonella Typhi | Vi capsular antigen; typhoid vaccine |
| Group B streptococcus | Neonatal sepsis and meningitis |
| Cryptococcus neoformans (fungus) | India ink stain; meningitis in AIDS |
Mnemonic for encapsulated organisms: SHiNE SKiS — S. pneumoniae, H. influenzae b, N. meningitidis, E. coli, Salmonella, Klebsiella, group B Strep.
Exotoxin mechanisms
Exotoxins are secreted proteins with precise molecular targets. Many A-B toxins use a B subunit to bind and an A subunit to act.
| Mechanism | Toxin (organism) | Effect |
|---|---|---|
| Inactivate EF-2 (ADP-ribosylation) | Diphtheria toxin; exotoxin A (Pseudomonas) | Halts protein synthesis — pseudomembrane, myocarditis |
| Inactivate 60S ribosome | Shiga toxin; Shiga-like toxin (EHEC) | Cell death; HUS |
| ↑ cAMP via Gs | Cholera toxin; heat-labile toxin (ETEC) | Rice-water diarrhea (Cl⁻ and water secretion) |
| ↑ cAMP via Gi inhibition | Pertussis toxin | Whooping cough, lymphocytosis |
| ↑ cAMP (adenylate cyclase itself) | Edema factor (B. anthracis) | Edema at the eschar |
| ↑ cGMP | Heat-stable toxin (ETEC) | Watery diarrhea |
| Cleave SNAREs — inhibitory neurons | Tetanospasmin (C. tetani) | Spastic paralysis, trismus, opisthotonos |
| Cleave SNAREs — ACh release | Botulinum toxin (C. botulinum) | Descending flaccid paralysis |
| Lyse membranes | α toxin (C. perfringens); streptolysin O; listeriolysin O | Myonecrosis, hemolysis |
| Superantigen | TSST-1 (S. aureus); SpeA (group A strep) | Toxic shock: fever, rash, hypotension, desquamation |
cAMP is the common thread for watery diarrhea; SNARE cleavage is the common thread for paralysis.
Endotoxin vs exotoxin
The distinction is a perennial Step 1 comparison.
| Feature | Exotoxin | Endotoxin |
|---|---|---|
| Source | Gram-positive and gram-negative | Gram-negative outer membrane only |
| Chemistry | Polypeptide | Lipid A of lipopolysaccharide |
| Release | Secreted | Released when bacteria lyse |
| Heat stability | Mostly labile (S. aureus enterotoxin is the exception) | Stable at 100 °C |
| Toxicity | High — tiny doses can kill | Lower |
| Immunogenicity | High; toxoid vaccines possible | Poor; no toxoid |
| Typical effect | Specific to the toxin | Fever, shock, DIC |
Toxoid vaccines exist for diphtheria and tetanus (in DTaP and Tdap).
Superantigens and toxin-mediated syndromes
Some of the most dramatic bacterial illnesses are caused by toxin alone, with few organisms present.
A traveler returning from Bangladesh has profuse painless watery diarrhea that looks like rice water. Stool shows curved, motile gram-negative rods. What is the molecular action of the responsible toxin?
- Rice-water stools and comma-shaped rods point to Vibrio cholerae.
- Cholera toxin ADP-ribosylates the α subunit of Gs, locking it in the active state.
- Adenylate cyclase stays on; cAMP rises in intestinal epithelium.
- CFTR opens, chloride and water pour into the lumen.
Answer. Permanent activation of Gs through ADP-ribosylation, raising cAMP and driving chloride secretion. Treatment is oral rehydration.