Cholera is a severe small intestine dehydration disease caused by the bacterium, Vibrio Cholerae. It is common in young children and causes severe vomiting and diarrhea. In many developing countries, children with cholera who do not receive rehydration therapy have a 50 percent chance of mortality. There are an estimated of 2-3 million cases per year, centered on the hot spots of Haiti, Africa, and the Bay of Bengal.  Currently, the only treatment for cholera is Dukoral, a vaccine that only provides short-lived immunity to the bacterium.

 

Andrew Camilli and his lab at Tufts Medical School are tackling many of the intricacies of cholera pathogenesis. Vibrio Cholerae is a water-born gram-negative bacterium (its outer cell wall consists of lipopolysaccharides) that can live in both aerobic and anaerobic environments. Only certain strains of the bacteria actually induce disease, which are denoted the O1 and O139. These two bacterial strains are pathogenic because they activate cholera toxin genes and pillus expansion genes; these genes are responsible for bacterial motility and invasion. 

 

The goal of the Camilli’s lab is to understand how the bacteria begin to develop pathogenic features such as activation of their toxin genes once inside the body. First, his lab looked at what features of the body caused the bacteria to transform. They studied the surface receptor VieS/VieA, which becomes activated when certain amino acids bind to the periplasmic membrane receptors. This explains why the amino acid rich small intestine is the perfect location for bacteria to proliferate.

 

Camilli also investigates the mechanisms that change the gene expression and overall chemistry of the organism after the bacteria is activated by the amino acids in the small intestine.  The lab had a hint that small RNA may play a role in gene activation, and they decided to implement RNA screening methods to see what RNAs were being expressed post activation of bacteria by amino acids.  They found an sRNA, IGR7, with the ability to regulate the maltose transporter operon, which is highly conserved amongst cholera strains.  They also found a subfamily of TarA and TarB sRNA that map to the “pathogenicity island” of the pillus. Together, these RNAs orchestrate the biochemistry and metabolism in cholera pathogenesis and may be potential targets for novel cholera therapies.

 

Camilli’s lab also studied overall gene expression and found that there were some genes, such as the chitin utilization genes ((2) c-di-GMP), which are activated when cholera is inside of the body. They surmised that these genes were activated during the late phase of the disease in order to prepare bacteria to live outside of the body once the organism had died. Future research will investigate the molecular intricacies of the process, but Camilli thinks that the signal transduction may involve ABC transporters.

 

The Camilli lab has extrapolated a variety of pathways that paint the picture of the pathogenesis of cholera. They think that understanding these biochemical and metabolic pathways is the key to the formulation of new therapies.