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 proposal describes a four-year plan to further establish the independent, translational research career for the candidate. In particular, the candidate, a trained physician and microbiologist, will continue his clinical research training and focus his time on his funded, collaborative project to define the natural history of P. aeruginosa changes during early CF airway infection. This project uses the P. aeruginosa clinical isolates, linked clinical data, and unique clinical research mentorship opportunities available from two locally-led, national studies of CF microbiology, the Early Antipseudomonal Therapy in Cystic Fibrosis studies (EPIC). Specifically, this 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. This mutation was associated in our preliminary studies with accelerated lung function decline. Perhaps related to this finding, preliminary evidence suggests that LasR mutation leads to increased resistance to the antibiotics used most often in CF therapy. 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 aim 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. Here, we also propose to compare results concerning LasR mutation with those for other common P. aeruginosa CF adaptive changes in this population. 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, and people with CF die at a median age of 37 years from chronic lung infections that limit their quality and length of life. This proposal describes a four-year plan to further establish the translational research career of the candidate, focused on the pathophysiology of chronic CF lung infections with the long-term goals of identifying and developing better treatments for this devastating disease. The project described here will define the differences among the bacteria that cause CF lung infections, and the relationship between these bacterial characteristics and lung disease progression, as a critical next step towards these goals.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02HL105543-03
Application #
8403705
Study Section
Special Emphasis Panel (ZHL1-CSR-U (O1))
Program Officer
Tigno, Xenia
Project Start
2011-01-21
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
3
Fiscal Year
2013
Total Cost
$100,116
Indirect Cost
$7,416
Name
University of Washington
Department
Pediatrics
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Brown, Perry S; Pope, Christopher E; Marsh, Robyn L et al. (2014) Directly sampling the lung of a young child with cystic fibrosis reveals diverse microbiota. Ann Am Thorac Soc 11:1049-55
Hoffman, Lucas R; Pope, Christopher E; Hayden, Hillary S et al. (2014) Escherichia coli dysbiosis correlates with gastrointestinal dysfunction in children with cystic fibrosis. Clin Infect Dis 58:396-9
Mayer-Hamblett, Nicole; Ramsey, Bonnie W; Kulasekara, Hemantha D et al. (2014) Pseudomonas aeruginosa phenotypes associated with eradication failure in children with cystic fibrosis. Clin Infect Dis 59:624-31
Mayer-Hamblett, Nicole; Rosenfeld, Margaret; Gibson, Ronald L et al. (2014) Pseudomonas aeruginosa in vitro phenotypes distinguish cystic fibrosis infection stages and outcomes. Am J Respir Crit Care Med 190:289-97
Cuthbertson, Leah; Rogers, Geraint B; Walker, Alan W et al. (2014) Time between collection and storage significantly influences bacterial sequence composition in sputum samples from cystic fibrosis respiratory infections. J Clin Microbiol 52:3011-6
Zerr, Danielle M; Qin, Xuan; Oron, Assaf P et al. (2014) Pediatric infection and intestinal carriage due to extended-spectrum-cephalosporin-resistant Enterobacteriaceae. Antimicrob Agents Chemother 58:3997-4004
Simon, Tamara D; Pope, Christopher E; Browd, Samuel R et al. (2014) Evaluation of microbial bacterial and fungal diversity in cerebrospinal fluid shunt infection. PLoS One 9:e83229
Sun, Xingshen; Olivier, Alicia K; Yi, Yaling et al. (2014) Gastrointestinal pathology in juvenile and adult CFTR-knockout ferrets. Am J Pathol 184:1309-22
Rogers, Geraint B; Hoffman, Lucas R; Carroll, Mary P et al. (2013) Interpreting infective microbiota: the importance of an ecological perspective. Trends Microbiol 21:271-6
Rogers, Geraint B; Cuthbertson, Leah; Hoffman, Lucas R et al. (2013) Reducing bias in bacterial community analysis of lower respiratory infections. ISME J 7:697-706

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