Grant: Project Grant

The incidence of the severe pneumonia that Legionella causes (Legionnaires' disease) is inexplicably on the rise - and deadly outbreaks have occurred in Toronto, Quebec City, and Calgary. Legionella can be isolated from the water systems of approximately 1 in 8 homes - and our aging population and aging infrastructure are only increasing the risk to health. Legionella pneumophila is the leading cause of waterborne outbreaks in the US, where it is estimated to cost over $400 million in direct hospitalization costs per year. Given worldwide incidence and trends, a similar relative impact on Canadian health is likely, if not as well quantified. Defining the molecular mechanisms by which Legionella replicates in our water and causes disease is essential to understanding and responding to these alarming trends. A central pillar of molecular pathogenesis is that bacteria inject proteins (effectors) into the host cell in order to modulate host proteins. We have recently uncovered a functionally novel class of effectors in Legionella pneumophila: "metaeffectors" (or "effectors of effectors") that target other effectors rather than host proteins. Metaeffectors are a gamechanger in the study of effector biology - they fundamentally change the way in which we study these important proteins and provide powerful connections to known biology from which we can build outwards from. In this proposal, we will leverage our discovery of metaeffectors to learn how effectors are regulated once inside the host cell. We will build outward from experimental beachheads of known biology to discover new aspects of the host-pathogen interface. Emerging data suggest that metaeffectors are a common feature of bacterial pathogens - meaning that we can no longer afford to overlook this biology. In addition to understanding Legionella metaeffectors, one key deliverable from this work is the establishment of a set of tools and approaches that will be broadly applicable to these other pathogens.