Bordetella Pertussis (whooping cough)

Overview
1. Respiratory tract infection
2. Primarily caused by Bordetella pertussis
  1. Also B. parapertussis and B. holmesii
3. Catarrhal phase
4. Paroxysmal phase
  1. Coughing fits
    1. Not normal coughing
    2. Several per hour 24-7
    3. Post tussive (coughing) comiting, hypoxia (neurological problems), malnutrition, secondary infections
5. Mainly affects infants
6. Major childhood infection
Re-emergence
1. Since mid-late 90's an apparent increase in cases of Pertussis reported
2. Disease in older children/adults
  1. Clear that immunity wanes over time
  2. Increased surveillance/better diagnostics
  3. Disease in older age groups contributing
  4. Very recently, large scale epidemics
Pathogenesis
1. Aquisition
  1. Infected droplets (host to host spread)
  2. Fomites?
2. Colonisation of ciliated tissue
  1. Not normal for most infection pathogens
  2. Bacterial multiplicaiton
  3. Inflammatory response
  4. Tissue damage
3. Adaptive immune response
  1. Innate immune cells recruited initially
  2. Antibody and T-cell mediated
4. No systemic element - completely confined to respiratory tract
5. Medium lived immunity - protected for life
6. Numerous complications
  1. Secondary/co-infections/pneumonia
  2. Seizures
  3. Significant physical damage/malnutrition
7. Only bind to cilia
8. Adhesins
  1. FHA
  2. Fimbriae
9. Toxins
  1. PT
  2. Adenylate cyclase
  3. Type III secretions
  4. LPS
10. Immune interaction/survival
  1. BrkA (resistance to serum killing)
  2. Iron acquisition systems
Bvg gene
1. 1. Detection of stimulus in periplasm
2. 2. Sensor kinase is triggered and auto-phosphorylation occurs
3. 3. Many phosphorylation sites
4. 4. BvgA is activated and binds to DNA motifs that increases or decreases transcription of target genes
5. Resting state - Bvg-
  1. Only flagella gene active
  2. Help for survival outside of host
  3. Silent below 27 degrees C
6. Active state - Bvg+
  1. Help for survival inside of host
  2. Activated at temperatures above 27 degrees and fully active at 37 degrees
  3. Many genes are being expressed
    1. Filametous haemagglutinin
    2. Pertussis toxin
    3. Fimbriae
    4. Adenylate cyclase
    5. BrkA/BrkB
    6. Type III secretion system
Evolution
1. A lot of genes have been lost by human adapted pathogens
2. Large number of IS elements have evolved
Speciation of pertussis and paraertussis
1. Evolution by genome reduction and rearrangement
2. Expansion of IS elements
  1. Rearrangement
  2. Deletion
  3. Gene inactivation
3. No gene acquisition
4. Differential gene expression is an important distinguishing feature
5. Evolution
  1. BP and BPP evolved from BB (B. bronchiseptica)
    1. BPP more recently than BP
  2. Likely involved host jump
  3. Coincident with urbanisation of humans
    1. Host density driven
    2. Loss of environment phase
    3. Chronic to acute
  4. Immunity-mediated competition
    1. BP evolved in presence of human associated BB
    2. BP evolved facing anti-BB selection pressure
    3. Displaced BB from human niche?
    4. BPP evolved facing anti-BP selection pressure
    5. But
      1. BP and BPP co-exist in the same niche
      2. BPP appears less rpevelent
Pertussis toxin
1. AB toxin
2. For years Pertussis was considered a toxin-mediated disease
3. ADP-ribosylating toxin (G-protein target)
4. Bvg+ phase expressed gene
5. Type IV secretion system
6. Probably delays recruitment of innate immune cells into lung
7. BP specific
8. Genes present in BB and BPP
  1. Pseudogene in BPP
9. Toxin produced when BB genes expressed in E. coli
10. Base pair differences between BB and BP promoters
  1. Considered silencing mutations in BB
11. Mutations in BP PT promoter increase binding by BvgA resulting in increased expression
Vaccines
1. 1940's - inactivating whole cell vaccine
2. Administered as DTP
  1. 3 primary jabs, school age booster
  2. Very young babies susceptible
3. Whole cell vaccine
  1. 'Toxoid' vaccine
  2. Chemical deactivation of whole cells
  3. WCV considered 'reactogenic'
    1. Fretfulness
    2. Injection site redness/soreness
    3. Headache
  4. Attribution to LPS (endotoxin) content
4. Acellular vaccine
  1. 3-5 purified components
  2. Improved safety profile
  3. Different mechanist of immunity?
  4. Phased implementation
  5. In UK, since 2004, all vaccinations use ACV
Future
1. Re-emergence
  1. Drop in vaccine coverage? - No
  2. Change in Pertussis?
    1. Greater virulence
    2. Avoidance of immunity
  3. Ascertainment issue?
    1. Heightened awareness leads to increased reporting
    2. But, spill over into infants is an indicator of increased level of disease
  4. Decreased vaccine efficacy?
    1. Significant outbreaks in countries using ACV
  5. Is Pertussis evolving to escape vaccine mediated immunity?
    1. Several polymorphisms in vaccine antigen genes
      1. PT promoter, type 1 to type 3
    2. In UK, switch from Fim2 to Fim3
      1. Altered immune clearance?
2. Acellular vaccines
  1. Increasing evidence that immunity to ACV ceases to be protective earlier than observed for infection/WCV
  2. >7 years susceptible to reinfection
  3. Changing epidemiology of Pertussis
  4. Increased exposure of infants?
  5. Booster programmed recommended
3. Are large scale outbreaks the future?
4. Can ACV continue to control Pertussis?
5. Will strains evolve further away from vaccine mediated control?

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Bordetella Pertussis (whooping cough)

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	Created by zambrella almost 11 years ago