Lung disease is the primary determinant of life expectancy and quality of life among people with the genetic disease cystic fibrosis (CF). The opportunistic Gram-negative bacterium Pseudomonas aeruginosa infects the respiratory tracts of most patients with CF, and infection with this pathogen is clearly associated with worse respiratory outcomes. P. aeruginosa infects CF airways early in life. Over many years, bacteria adapt to the CF airway environment and stimulate inflammatory responses that are ineffective in eradicating the infection, yet damage airways. The development of strategies to prevent P. aeruginosa colonization and eliminate chronic infection will require an understanding of the natural history of the bacterial contribution to CF lung disease. This ancillary grant proposal describes a collaborative project including CF clinicians, microbiologists, and epidemiologists that will make use of the unique resources generated from two large, interrelated, ongoing multicenter studies of CF microbiology, known as the Early Antipseudomonal Therapy in Cystic Fibrosis studies (EPIC). We propose to use the P. aeruginosa clinical isolates, linked clinical data, and unique clinical research mentorship opportunities available from the EPIC trials to study the natural history of P. aeruginosa adaptation to the CF airway. Specifically, the proposed project will define the clinical relevance of infection with P. aeruginosa carrying a newly-identified adaptive change: inactivating mutation in the gene encoding the major transcriptional regulator LasR. In a recent single-center, cross-sectional study, we found this mutation to occur early during CF chronic airway infection, on average two years earlier than mucoidy (the best-described P. aeruginosa CF adaptive change), yet with a similar prevalence. Furthermore, LasR mutant infection was associated with accelerated lung function decline. Perhaps related to this finding, preliminary evidence suggests that LasR mutation leads to increased resistance to the three classes of antibiotic used most often in CF therapy: ?lactams, aminoglycosides, and fluoroquinolones. Conversely, LasR mutants are more susceptible in vitro to at least two classes of metabolic inhibitors, suggesting alternative therapeutic strategies for patients infected with these isolates. Thus, the emergence of LasR mutation during chronic P. aeruginosa CF airway infections may serve as a marker for advancing disease, and novel therapies could be developed for patients carrying these adaptive mutants. However, to address the utility of these approaches, our preliminary epidemiologic findings must be validated in a larger, multicenter population. We propose to define the prevalence and associated clinical features of LasR mutant P. aeruginosa infection among the young children enrolled in the EPIC trials, to test the hypothesis that LasR mutation occurs relatively commonly and early during P. aeruginosa CF infections, and is associated with preceding antibiotic exposure, accelerated decline in lung function, and more frequent respiratory exacerbations. The results of this study will clarify the natural history of CF lung disease, and may lead to improvements in current CF therapeutic regimens.

Public Health Relevance

Cystic fibrosis (CF) is the most common genetic disease of Caucasians. People with CF die at a median age of 37 years from chronic lung infections that limit their quality and length of life. This project will examine the differences among the bacteria that cause CF lung infections, and the relationship between these bacterial characteristics and lung disease progression. The goal of this project is to better understand the pathogenesis of CF lung disease so that better treatments can be developed.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098084-04
Application #
8316180
Study Section
Special Emphasis Panel (ZHL1-CSR-G (M1))
Program Officer
Banks-Schlegel, Susan P
Project Start
2009-09-11
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$383,041
Indirect Cost
$42,689
Name
University of Washington
Department
Pediatrics
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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