PROJECT SUMMARY Dr. Bollyky is a mid-career investigator who has developed a successful, translational research program focused on bacteriophages – viruses that infect bacteria - and bacterial wound and airway infections. He is also a highly productive research mentor, serving as a director of the physician-scientist training program for the medical residency program as well as training numerous residents, fellows, and medical students in his own lab. The goal of this K24 is to provide Dr. Bollyky with protected time to grow his patient-oriented research program and mentor additional clinical fellows, junior faculty and other trainees in patient-oriented research. The proposal also provides for dedicated time and resources to help Dr. Bollyky enhance his own mentoring skills, obtain scientific and career guidance from an advisory committee, sharpen his skills in vaccinology and microbiology, and expand his knowledge and technical skills in human clinical studies. The scientific focus of this work is bacteriophages – viruses that infect bacteria – and their impact on bacterial infections. Phages are abundant in the human body but their impact on human health is largely unknown. The Bollyky lab has recently reported that phages produced by the major bacterial pathogen Pseudomonas aeruginosa (Pa) promote chronic Pa infections. In particular, they have identified a novel mechanism by which filamentous Pf phages produced by Pa contribute to antibiotic tolerance by functioning as structural elements in Pa biofilms – slimy communities of bacteria and polymers that allow bacteria to colonize airways and other surfaces. Pf phages organize host and microbial polymers in ways that produce a robust biofilm that resists penetration by antibiotics, leading to antibiotic resistance. Their team recently published that Pf phages are associated with heightened antibiotic resistance in patients with cystic fibrosis (CF), a genetic disease associated with thick, tenacious sputum and chronic lung infections with Pa. It may be possible to protect against Pa infection by targeting Pf phages. The Bollyky Lab recently developed a vaccine that targets Pf phages to prevent Pa infections. However, it is unclear whether antibodies against Pf phages naturally occur and whether these are protective against Pa infection. Here, Dr. Bollyky will test the hypothesis that Pf phages contribute to antibiotic resistance and chronic infections while Pf antibodies protect against this. In Aim 1 they will define how Pf phages contribute to antibiotic tolerance in Pa biofilms. In Aim 2 they will define how Pf antibodies protect against Pa infections. Finally, in Aim 3 they will determine whether Pf and anti-Pf phage antibodies influence clinical outcomes in patients with CF. Together, these studies will give rise to novel therapeutic targets and treatment strategies against Pa biofilm infections and launch the careers of multiple young physician scientists. Protected time for caree...