Grant: Project Grant

A central pillar of molecular pathogenesis is that bacteria inject effector proteins into the host cell where they modulate host proteins. Each effector, however, does not function in isolation. Studying how effectors function in concert is an essential next step in understanding the molecular events that lead to microbial disease. We previously identified a new virulence factor landscape in Legionella pneumophila that is essential for understanding how the pathogen interacts with its hosts. Metaeffectors (or "effectors of effectors") target other effectors rather than host proteins. In an effort to generalize our findings beyond L. pneumophila, we have spent the last 5 years identifying metaeffectors in other pathogens and developing approaches to systematically predict and characterize effector activity and interactions. With this knowledge and a suite of new tools, we are now well equipped to study metaeffectors within the context of infection and study how misregulation of effectors can alter the trajectory of disease. We will focus on two pathogens: Legionella pneumophila, the causative agent of Legionnaires' disease-a severe often-fatal pneumonia, and Chlamydia trachomatis, the most prevalent sexually transmitted disease in Canada and a common cause of incurable blindness in the developing world. This summer alone, explosive outbreaks of Legionnaires' disease have occurred in Harlem, New York (114 cases, 90 hospitalized, 7 deaths) and London, Ontario (94 cases, 86 hospitalized, 4 deaths). L. pneumophila and C. trachomatis replicate intracellularly within host cells but use different machinery to inject distinct effector arsenals into their hosts. The inclusion of each pathogen brings a set of complementary strengths to our studies that we will leverage to generalize our findings and make important advances within this new fundamental aspect of molecular pathogenesis.