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