Grant: CIHR Fellowship

A large proportion of human disease results from bacterial pathogens that invade and infect host cells. Diseases like malaria and tuberculosis result from such intracellular infection and cause widespread illness and premature death worldwide. A versatile intracellular pathogen, Salmonella enterica, is capable of infecting diverse hosts and causing different diseases. In humans, S. enterica strains can cause typhoid or gastroenteritis, both responsible for much morbidity and mortality throughout the world. A central aspect for pathogenesis of S. enterica and other bacterial pathogens is their ability to hijack host cell processes for their own benefit. Upon encountering a human cell, Salmonella delivers a choreographed series of virulence factors (also known as 'effector' proteins) into the cells using needle-like structures. These effector proteins are key players that hijack natural host cell processes and ensure survival, invasion and replication of these types of bacteria. To date we only know bits and pieces of the impact of these effector proteins and their role in Salmonella invasion on host cells. I am proposing here to test the effects of Salmonella on a variety of host processes. The central analytical method that I will use to investigate this is mass spectrometry. This powerful technique allows us to monitor all or most of the early processes downstream of invasion. Thereby I hope to tease apart the effects of these closely-related effectors, and to look at the impact of all the effectors on human proteins that we know are targeted by Salmonella. So the studies proposed here will allow us to make a quantum leap forward in our understanding of how Salmonella controls its host. In particular, a detailed map of key players and their actions during Salmonella invasion will be constructed. Ultimately, therapeutic strategies for treating salmonellosis can be based on key players that will be identified and characterized in these studies.