;Structural studies into novel membrane associated virulence factors of Legionella pneumophila

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Bacteria are tiny organisms that live in a wide range of environments on the earth, including humans and animals, where they have both a positive and negative impact on health. In this application, we propose a number of experiments that will help us to understand certain aspects of how dangerous bacteria are able to persist in the environment and cause disease in humans. We will specifically study the bacterium Legionella pneumophila, which is ubiquitous in aquatic systems (e.g. rivers, reservoirs, hot/cold water supplies, cooling towers) and highly prevalent in large buildings such as hospitals and hotels. L. pneumophila causes Legionnaires' disease (an often-fatal pneumonia), and Pontiac fever, (a milder flu-like disease) and rates of infection are increasing each year, both in the UK and globally. Within the environment L. pneumophila lives within biofilms where it clumps together with other bacteria and is covered in a defensive mesh. This protects it from external factors such as dehydration but also from attack by other organisms and antibacterial compounds. However, single celled organisms called amoebae can still graze on these bacteria and L. pneumophila has developed strategies to survive by going inside them and hiding away from attack. Once inside these hosts, L. pneumophila lives within a membrane-bound compartment (the Legionella containing vacuole; LCV), where it evades detection. Unfortunately, some types of human lung cells share similarities with amoebae and therefore Legionella causes disease when humans come into contact with contaminated water. L. pneumophila secrete many proteins outside of the bacterium that allow it to sense the outside world, interact with other organisms and also manipulate host amoebae and human cells so that they can survive inside them. For example, the 'type II secretion system' (T2SS) uses a syringe-like mechanism to export proteins that help form biofilms and enables L. pneumophila to become fully virulent. We have identified a unique class of these proteins that once exported are able to either bind to the surface of L. pneumophila, helping it stick to other bacteria in biofilms and recognize host cells; or, when inside a host, bind to the Legionella containing vacuole, helping it to become camouflaged so that it is not detected. Understanding the details of how these proteins function and why they localize to their specific membranes will be crucial to further our knowledge of L. pneumophila infection. Likewise, these studies may also reveal common pathways for infectious disease used by other bacteria, which may in turn help us design compounds which disarm L. pneumophila and other dangerous pathogens.