26 - Vibrio cholerae Flashcards
Clinical features of cholera
- Incubation 18h to 5 days
- Very severe watery diarrhoea (rice water stool)
- Death due to dehydration or electrolyte imbalance
Two patterns of disease
Endemic or epidemic
Endemic disease
- Seasonal outbreaks
- Children most at risk (no pre existing immunity)
Epidemic disease
- Intro of new infection or strain
- All ages
- More severe
- Linked to natural disasters
Spread of cholera
- Faeco oral spread
- Often within families
- Asymptomatic shedding common, leading to contamination of water supply
Vibrio cholerae
- Gram negative comma shaped with flagellum
- Horizontal gene transfer important - 2 chromosomes (Ch2 is ‘domesticated plasmid’)
- Contains super integron
Horizontal gene transfer
- Naturally competent (transformation)
- Frequently infected by phages (transduction)
- Multiple plasmids (conjugation)
Super integron
Large integron with 179 cassettes, many of which encode virulence determinants
Integron
Genetic elements with the ability to capture genes (into expression cassette), including those encoding antibiotic resistance or virulence factors by site specific recombination
Ecology
- Saline coastal waters and estuaries
- Lives in association with zooplankton and shellfish
- During periods of nutrient deficiency –> viable, non-culturable form in biofilms
- Favourable conditions (zooplankton bloom) –> proliferate –> humans ingest water
- Outbreaks occur through faecal contamination of water
Chitin from shellfish
Induces competence for transformation
V. cholerae T6SS
- Uses as a weapon to kill surrounding bacteria and ‘steal’ their DNA by transformation
Three distinguishing characteristics
- Key role for genetic exchange between strains/species
- Rapid modulation of gene expression in response to external stimuli
- Toxin production
Process of colonisation
- Colonises the gut mucosa, does not invade
- Flagellum moves the bacteria towards the epithelial surface
- Cholera toxin coregulated pilus (TcpA) mediates attachment to mucosa
Acquisition of cholera toxin
- Non-pathogenic strains are infected by a bacteriophage (Vibrio Pathogenicity Island phage - VPIΦ)
- VPIΦ encodes TcpA
- TcpA then acts as receptor for a second bacteriophage, CTX Φ
- CTX Φ has genes for cholera toxin (CTX)
Pathway of cholera toxin
- Single toxic active A subunit attached to a ring of five identical cell-binding B subunits
- B subunits bind to the epithelial cell surface receptor, ganglioside GM1
- Toxin is endocytosed and transported to ER
- CT-A1 dissociates from B pentamer to enter cytosol, where is activates the Gsα subunit of guanine nucleotide-binding regulatory protein
- This reaction locks adenylate cyclase in an activated state, resulting in enhanced cyclic AMP (cAMP) production.
End result of cholera toxin pathway
- cAMP activates protein kinase-A (PKA).
- Activation of PKA inhibits NaCl absorption through Na+/H+ exchanger, with decrease in sodium uptake and an increase in chloride and bicarbonate export.
- Water follows this ion gradient
to produce a net fluid loss.
Host genetics and susceptibility to cholera
Cholera toxin (CT) interaction with host cells depends on the person’s blood group and secretor status
Role of blood group and secretor status in cholera
- In ‘secretors’, blood group antigens are expressed on intestinal epithelial cells.
- Blood group A-antigens have a low affinity for CT, and CT is therefore more easily ejected by the peristaltic movement of the intestine.
- Therefore secretors with blood group A are protected from severe disease
- Group O can bind CT strongly, therefore individuals with blood group O have a high risk of severe disease
Quorum sensing in regulation of virulence factor expression
- Expression of TcpA, CTX and several other virulence, factors is under quorum sensing control.
- Expression is increased at low cell density and repressed at high cell density
which group of cholera has caused all pandemics
Serogroup O1
Prevention
- Sanitation infrastructure, municipal water systems
- Oral vaccines incorporating inactivated V. cholerae +/-toxin B subunit
Treatment
- Fluid replacement
- Antibiotics
- Zinc for young children
Outbreak management
- Safe drinking water, sanitation hygiene
- Vaccination stockpiles
