Grant: Project Grant

Large Clostridial toxins (LCTs) are a family of extraordinarily potent bacterial toxins. For example, the most common hospital-acquired diarrhea in developing countries is caused by Clostridioides difficile and its two LCTs TcdA and TcdB. These toxins cause tissue damage by modulating host cell function and behavior in order to promote tissue invasion and proliferation of pathogens. But before doing so, LCTs must gain entry into the cell. They enter human cells by exploiting cell-surface molecules normally present in healthy tissues and use these for docking onto the cell. However, in most cases it is not clear which receptors these toxins use to gain entry. Although recent studies have started to identify receptors for C. difficile toxins, there are many other LCTs whose receptors are not known. In this project, we will use modern genome engineering tools to identify human receptors for multiple LCTs from several different pathogens. We will then characterize at the structural level how LCTs engage their receptors. Finally, we will engineer toxins to bind new receptors on the cell surface in order to develop next-generation therapies for human diseases.