Figure 6. Regulation of V. cholerae virulence cascade and mucosal escape.

A) When V. cholerae contacts host epithelial cells, expression of the phosphodiesterase VieA is upregulated, resulting in a decrease in intracellular c-di-GMP concentration. In turn, low c-di-GMP concentration induces expression of toxT, which controls the production of V. cholerae’s major virulence factors, toxin co-regulated pilus (TCP) and cholera toxin (CT). Production of TCP and CT also depends on two transmembrane transcriptional regulators, ToxR and TcpP, as well as the cytoplasmic regulators AphAB and ToxT. TCP is a type IV pilus that facilitates colonization of the intestinal epithelium, while CT is a secreted toxin that causes constitutive cyclic AMP production in host epithelial cells, leading to profuse secretion of chloride and water into the gut lumen.

B) During later stages of infection, as the population density increases and cells reach stationary phase, production of the starvation/stationary phase alternative sigma factor RpoS and the quorum sensing master regulator HapR are induced. These regulators trigger flagellar assembly and chemotaxis, which foster exit from the host. Additionally, the population of V. cholerae cells in the small intestine becomes bifurcated; half of the cells continue to show high expression of virulence genes (represented by bottom cell), while the other half shows downregulation of virulence genes.