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Diphtheria toxin as most important virulence factor

  • Toxin affects heart, peripheral nerves, and kidneys
  • Disease caused by strains that release diphtheria toxin
  • Abs cannot reverse effects of toxin
  • Erythromycin helps eradicate organism and prevent transmission but does not stop disease in vivo
  • Must give antitoxin early to prevent disease from progressing


Diphtheria toxin in prevention of diphtheria 

  • Toxin given as a vaccine along with tetanus in DTap or Tdap vaccine
    • Made from purified toxin treated with formaldehyde, which destroys toxicity but not immunogenicity
  • Antitoxin from horse Abs is necessary for treatment of active diphtheria and must be given ASAP
  • > 4 days before antitoxin - death rate as high as in untreated patients (20%)
  • Must get antitoxin from state health dept or CDC


Safety & efficacy of DTap/Tdap vaccines

  • Diphtheria vaccine = safe and effective
  • Whole cell pertussis vaccine (no longer used):
    • Series of nasty side effects
    • Including neurological sequelae, death
  • Acellular pertissus vaccines (aP)
    • Less likely to provoke adverse events


20 year old with all childhood DPT vaccines but none since - what amount of disease would they develop? 

  • Would probably be somewhat protected but still get a mild case of the disease, as immunity wanes
  • This is why aP is included with DT vaccine recommended every 10 years 
  • Bigger issue may be transmission of mild disease to immunocompromised individuals like infants
  • Diphtheria is rare in US, so chance of encountering infected individual is miniscule


MOA of diphtheria and pertussis vaccines protection against disease

  • Diphtheria:
    • Toxoid made from purified toxin treated with formaldehyde 
    • Conveys immunogenicity to recipient without toxicity
    • Host makes anti-toxin Ab
  • Pertussis:
    • Merthiolate, heat, or formalin-killed cells from fully virulent B. pertussis used
    • Host makes Ab to many of the toxins


Other virulence factors of B. pertussis 

  • Pertussis toxin:
    • A portion transferse ADP-ribose of NAD onto inhibitory subunit of adenylyl cyclase --> constitutive activation --> increased cAMP
    • Cholera toxin is similar, but stimulates S subunit of adenylyl cyclase
  • Tracheal cytotoxin:
    • Activates iNOS in nearby cell that kills off cilia (hence coughing)
    • Part of murein cell wall
  • Adenylyl cyclase toxin
    • Adverse effect on trafficking of macrophages
  • Filamentous hemagglutinin (FHA)
    • Role in attachment to ciliated respiratory epithelial cells


Problems encountered in making lab/clinical diagnosis of Diphtheria/Pertussis

  • Both are slow-growing
  • Don't wait for diphtheria diagnosis - give antitoxin based on clinical suspicion (wet mouse smell) before lab results
  • Antimicrobials given early in stage of whooping cough can ameliorate disease


Wait for lab diagnosis of diphtheria/pertussis before treating?

  • NO
  • Patient may die if they have diphtheria
  • And better outcomes if erythryomycin is given in catarrhal stage of pertussis 


Environmental factors influencing expression of C. diphtheriae and B. pertussis toxins

  • Diphtheria toxin:
    • Regulated by iron
    • Increase in iron in environment will shut off toxin synthesis 
  • Pertussis toxin:
    • Virulence  regulated by genes in a locus called vir
    • Vir is master regulator that can swithc on and off expression of virulence factors
    • On-off switch of vir locus (phase variation) + environmental factors (modulation) control expression of virulence factors


Value of abx usage in diphtheria/pertussis 

  • Even though major manifestations are due to toxins, treatment with abx: 
    • Can eliminate carriage and subsequent transmission
    • Can reduce bacterial load producing toxins (may reduce severity of disease)
    • Are critical prophylactic treatment for contacts
  • Give erythromycin (B. pertussis is suceptible to penicillin but it can't reach the site of infection)


People who should not be vaccinated with whole cell pertussis vaccine

  • Whole cell pertussis vaccine no longer available
  • Likely contraindicated for those with compromised immune systems or who had previously had a serious adverse event (e.g. seizure)
  • Acellular vaccine probably less efficacious, but has been shown to have fewer adverse side effects and is safer for all ages