Characterizing the biological functions of novel hybrid AB5 toxins discovered in Salmonella

Many bacterial pathogens cause disease to humans by producing toxins. Vibrio cholerae causes the deadly disease cholera upon production of the aptly named cholera toxin. Certain types of Escherichia coli can produce a Shiga toxin that can lead to kidney failure. Both toxins are different in activity, yet both are members of the same toxin family known as AB5 toxins. Toxins in this family are composed of one A subunit and five B subunits. The A subunit is responsible for causing harm to human cells, while the B subunits maneuver the toxin to its specific target. Our lab studies the AB5 toxin produced by Salmonella Typhi known as the typhoid toxin, which is responsible for typhoid fever. We have recently discovered that certain Salmonella strains encode a remarkable toxin that is a "hybrid" of typhoid toxin and Shiga toxin; it contains an A subunit like that of a Shiga toxin and a typhoid toxin-like B subunit. A second hybrid toxin with a Shiga toxin-like A subunit and a cholera toxin-like B subunit was identified. We determined that these are two genuine toxins, but nothing is known about their biology or their role in causing disease. This project will use a multi-disciplinary approach across biochemistry, microbiology, and cell biology to study the function and activity of these toxins, and their role in how these certain Salmonella strains can cause damage to human cells. The knowledge gained from this project will provide insight into how the AB5 toxin family has evolved. Furthermore, bacterial toxins are under study as therapeutics to treat non-bacterial diseases. These toxins will demonstrate how different A and B subunits assemble into full AB5 toxins, potentially opening the door to developing drug-delivery tools with customizable activity and cell targets.