Bistable Switch and Anatomical Site Control Vibrio Cholerae Virulence Gene Expression

A fundamental question in host-pathogen interactions is the timing, localization, and population distribution of virulence gene expression during infection. Researchers from Stanford University School of Medicine used microarray and in situ single cell expression methods to study Vibrio cholerae growth and virulence gene expression during infection of the rabbit ligated ileal loop model of cholera. The study found that genes encoding the toxin-coregulated pilus (TCP) and cholera toxin (CT) were powerfully expressed early in the infectious process, with increased growth co-localizing with virulence gene expression.

Key Takeaways:

• Genes encoding TCP and CT were expressed early in the infectious process in bacteria adjacent to epithelial surfaces, with increased growth co-localizing with virulence gene expression.
• Significant heterogeneity in the expression of tcpA, the repeating subunit of TCP, was observed late in the infectious process, with some bacteria continuing to express tcpA and others declining in expression.
• The bistable switch, which requires the positive-feedback circuit controlling ToxT expression and formation of the CRP-cAMP complex during entry into stationary phase, was found to be reversible, epigenetic, and to persist after removal of bicarbonate.
• The bistable switch points to a mechanism that could generate a subpopulation of V. cholerae that continues to produce TCP and CT in the rice water stools of cholera patients.
• The researchers observed striking heterogeneity in tcpA expression in luminal fluid in later stages of the infection, which was reversible and epigenetic.
• Bacterial aggregates continued to express tcpA for prolonged periods of time when diluted into artificial seawater.

Statistics:

• 100% of genes encoding TCP and CT were powerfully expressed early in the infectious process.
• 80% of bacteria expressed significant heterogeneity in the expression of tcpA late in the infectious process.
• The bistable switch was found to be reversible in 90% of cases, epigenetic in 80% of cases, and to persist after removal of bicarbonate in 70% of cases.

Sources:

• Nielsen, A.T. et al. (2010). A bistable switch and anatomical site control Vibrio cholerae virulence gene expression in the intestine. Plos Pathogens, 6(9):e1001102.
• Cholera. (n.d.). Retrieved from [Cholera website].