What traits distinguish Pseudomonas aeruginosa strains that successfully colonize cystic fibrosis airways?

Fellow: Cara Forsberg, PhD
Genome Sciences

Mentor:  Colin Manoil, PhD
Professor, Genome Sciences

The goal of this study is to identify bacterial traits that enable Pseudomonas aeruginosa to cause chronic infection within the airways of patients with cystic fibrosis. While the host response and the lung microenvironment may also influence the outcome of infection, there are likely bacterial factors that promote chronic infection in the lung. Once established, these infections are highly resistant to antibiotic therapy and lead to a dramatic decline in lung function. Therefore, understanding the bacterial factors that enable successful long-term infection may identify new therapeutic targets. We will identify bacterial traits that correlate with infection outcome by characterizing two classes of P. aeruginosa isolates obtained through the Early Pseudomonas Infection Control (EPIC) clinical trial; “eradicated” isolates were easily cleared from the lung, whereas “persistent” isolates were not cleared despite continued antibiotic treatment. To discover potential differences between these strains we will measure their growth in response to various stress and metabolic conditions (Aim 1a), and in the presence of common co-colonizing bacterial species (Aim 1b). The CF lung represents a polymicrobial community, especially in young patients, and the eventual success or clearance of P. aeruginosa isolates may be influenced by their ability to compete with neighboring bacteria in the lung. These techniques will identify differences in response to various environmental conditions. To complement these approaches, we will also assess the performance of persistent and eradicated strains in two independent animal models of infection (Aim 2). Both approaches will likely identify differences among these isolates, which may be conferred by strain-specific (“accessory”) genes. We will identify accessory genes from sequenced eradicated and persistent isolates that are associated with infection outcome and directly assess a role for these genes in response to environmental and infection conditions (Aim 3). The study of isolates known to have different infection outcomes may uncover bacterial factors central to the establishment of chronic infection, which could lead to the identification of targets for novel preventative therapies.