Chronic infections are a major and rising medical challenge, often characterized by varying pathogen virulence and drug resistance profiles. Pseudomonas aeruginosa (PA) is a key driver of chronic infection mortality, including in our focal system of lung infections in Cystic Fibrosis (CF) patients. While PA has been studied extensively, the role of naturally occurring bacteriophages (phages) in shaping the evolutionary dynamics of chronic infections has been largely overlooked. It is recognized that within the CF lung there are high levels of phage, and in vitro work suggests that phage are potential drivers of bacterial diversity and of shifts in virulence. Phages bind to specific bacterial surface factors to initiate infection, including receptors that are important for virulence and antibiotic resistance, such as LPS, type IV pili, or efflux pumps. Thus phages can in principle impart selection on a pathogenic bacterium that impacts virulence and antibiotic resistance changing the trajectory of chronic infections. While naturally present phages have been largely overlooked in an infection context, phage therapy continues to draw attention and mixed results. In order to understand the drivers of pathogen evolution in an infection context, and to assess the potential for phage therapy as a curative and/or selective agent, it is essential to map the selective impacts and molecular targets of phages within infection settings. The overarching hypothesis of this study is that introduced and endemic phages shape the evolution of pathogen surface factors, which in turn define pathogen virulence and drug / phage resistance. This project will test this hypothesis using an array of genomic, phenotypic and modeling techniques with the goal of opening paths towards improved mechanisms of control.
For patients with compromised health (e.g. people with cystic fibrosis or diabetes), chronic infections are a major challenge as they are often non-responsive to antibiotics that kill the pathogen in vitro. In this proposal, we aim to understand the evolutionary dynamics that endemic and introduced phages impose on bacteria during chronic infections, and their consequences for critical clinical phenotypes of resistance and virulence. By developing a better understanding of the evolutionary dynamics of chronic infections, we will open the path towards improved mechanisms of control.