Cystic fibrosis (CF) is the most common life-shortening genetic disorder in the white population in the U.S. Much of the morbidity and mortality in CF is caused by the bacterium Pseudomonas aeruginosa. Newly infected children often eradicate P. aeruginosa from their airways with the aid of aggressive antibiotic therapies. However for poorly understood reasons, a substantial proportion of P. aeruginosa strains persist despite these therapies and can be intermittently recovered from respiratory specimens over subsequent years. After a variable period of intermittent infection, some strains of P. aeruginosa eventually cause chronic infection (during which the bacterium is reproducibly and consistently grown from respiratory specimens). Once P. aeruginosa infection establishes chronicity, the bacterium cannot be eradicated with antibiotics even if it is sensitive when tested ex vivo and exposed to prolonged courses of intravenous antibiotics. The net result is a slowly progressive deterioration of lung function that frequently culminates in death or lung transplantation. Given the severe clinical consequences, new approaches are needed for identification of bacterial biomarkers that identify strains at high risk for causing chronic infections. These biomarkers would allow (i) identification of patients likely to progress to chronic infections so they can be targeted for aggressive interventions, and (ii) identification of molecular targets of P. aeruginosa essential for progression to chronic infection. These targets would be strong candidates for inhibition by small-molecules. Since current therapies are sub-optimal, new approaches for preventing chronic infections in cystic fibrosis are needed. Which bacterial factors are responsible for persistence? Approximately 15% of the P. aeruginosa genome varies from strain to strain. These genes, which confer strain-specific traits, are together referred to as the “accessory genome.” Intriguingly, pathogenic variability has been traced to the accessory genome in acute P. aeruginosa infections such as ventilator-associated pneumonia. The role of the accessory genome in CF is less clear, but specific accessory genes are over-represented in CF isolates. We hypothesize that the presence of specific accessory genes in some P. aeruginosa strains allows them to persist in the CF airways. The goal of this project is to use comparative genomic methodologies to test this hypothesis and identify these genes. To test our hypothesis, we will utilize the Early Pseudomonas Infection Control (EPIC) Clinical and Observational Trials, which consist of 249 patients from multiple sites followed over a median of almost seven years since initiation of the trial. We propose to use the EPIC cohort to test our hypothesis by completing the following specific aims: (1) In children with CF newly infected P. aeruginosa, we will identify accessory genes that distinguish isolates that persist to cause intermittent infections from those that are eradicated. (2) In children with CF intermittently infected with P. aeruginosa, we will identify accessory genes that distinguish isolates that cause progression to chronic infection from those that do not.
|Effective start/end date||9/16/15 → 6/30/19|
- National Heart, Lung, and Blood Institute (1R21HL129930-01)
Inborn Genetic Diseases