Virulence inducing signals of Vibrio cholerae

Vibrio cholerae is a bacterial pathogen endemic to many regions of the world where it iscommonly found in the aquatic environment. When water contaminated with V. cholerae isingested by a human host, the bacteria colonize the small intestine where they produce choleratoxin, resulting in disease. Virulence genes, including cholera toxin, are expressed at a veryhigh level near the epithelium of the small intestine, but not in the lumen. In the lumen, thebacteria encounter high concentrations of bile, a negative regulator of virulence genes. Whenthe bacteria penetrate the mucus layer and approach the epithelium, bile levels decrease andthey encounter bicarbonate, a positive regulator of virulence genes. They also meet with risinglevels of antimicrobial peptides (APs), which are produced by the intestinal epithelial cells aspart of innate immunity. Our laboratory recently found that several cationic APs further elevatevirulence gene expression in combination with bicarbonate treatment. Therefore, wehypothesize that V. cholerae uses antimicrobial peptides from intestinal epithelial cells in thehuman host as a key spatial signal to increase virulence gene expression. The objective of theproposed studies is to better understand the role of this signal in cholera pathogenesis. Theobjective of this proposal will be accomplished by pursuing two specific aims: 1) Characterizethe molecular mechanism(s) by which antimicrobial peptides enhance virulence geneexpression; and 2) Determine the consequences of responding to these antimicrobial peptidesignals in the pathogenesis of cholera. Completion of this two-year study will produce afoundation of knowledge on a previously uninvestigated signal that enhances virulence geneexpression in this important bacterial pathogen. This will add to our greater understanding ofthe spatial cues that govern the production of virulence factors by V. cholerae.