Grant: CIHR Fellowship

Diarrheal disease affects 1.7 billion people every year, killing more than 760,000 children worldwide. A leading cause of diarrhea are the attaching and effacing (A/E) pathogens, which include both bacteria that infect humans (such as enterohemorrhagic Escherichia coli or EHEC, the cause of "hamburger disease") and bacteria that infect mice (Citrobacter rodentium or CR). The first major hurdle that A/E pathogens must overcome to infect their hosts is the gut microbiota, which is a microbial community of trillions of bacteria present in the mammalian digestive tract. Next, A/E pathogens face the intestinal mucosal surface, which represents another tightly regulated barrier against pathogens. To overcome these barriers, A/E pathogens have evolved to secrete toxins directly into target cells using complex machines called secretion systems, such as the type 6 secretion system (T6SS). My research will examine how A/E pathogens use this sophisticated mechanism to successfully colonize the gut. I propose to show how A/E pathogens use the T6SS to shape the gut microbial community by killing specific microbiota members. I will first use an animal model of infection to identify whether the T6SS is crucial for the success of CR infection, and to measure how this secretion system affects the abundance of other bacteria in the gut. I also aim to reveal for the first time how EHEC manipulates not only the gut microbiota, but also the host cell, thus creating a suitable niche for bacterial survival. I will achieve this using proteomic techniques to explore the interactions between secreted bacterial toxins and host proteins. Finally, I will investigate whether interfering with this toxin-host interaction blocks EHEC infection. Together, these experiments will improve our understanding of the interactions between the gut microbiota, the host and A/E pathogens. Importantly, this research may lead to new therapeutic approaches for treating infectious diseases.