Grant: Project Grant

Many bacterial pathogens use hair-like filaments called type IV pili (T4P) as mini grappling hooks to stick to their hosts and rapidly spread. T4P are thus potential targets for new antimicrobial therapies such as vaccines. Each filament is made of thousands of small lollipop-shaped proteins called pilins. The "stick" of the lollipop is very conserved and has a number of important functions. It stores pilins in the cytoplasmic membrane; forms the inner core of the pilus; and acts as a recognition domain for sensor proteins that monitor pilin inventories, so more are made only if needed. We will investigate how these monitoring systems recognize pilins, so we can fool them into shutting down even if there aren't enough pilins available. In contrast, the "lollipop" part of a pilin is diverse, making it harder to design a vaccine that will cover all possible "flavours". We are trying to understand the causes and consequences of pilin diversity, to inform the design of new treatments. We study Pseudomonas aeruginosa (Pa), a pathogen designated by the World Health Organization as a critical priority for new therapies due to its high level of resistance to antibiotics. We searched thousands of Pa DNA sequences to find all of its pilin flavours, and constructed a panel of different pilins in a common genetic background. This unique and expandable resource will allow us to ask how the immune system "sees" different pilins - when is recognition lost? We think that diversity arises from attempts to escape from viruses that stick to the pili. Changing a pilin's sequence or hiding it with sugars blocks attachment. Remarkably, some viruses can bind to very different pilins, suggesting they see a non-obvious common feature. We will characterize how those viruses interact with diverse pilins. They are of interest as therapeutics, as they can kill multidrug resistant bacteria. Together, this work will give us an unprecedented understanding of how pilus diversity is shaped.