There is an increasing recognition that the airways of persons with cystic fibrosis (CF) typically harbor complex polymicrobial communities that include numerous bacterial species. It is unknown, however, how changes in these communities relate to the progression of lung disease. More specifically, it is unclear how changes in the structure and/or activity of airway bacterial communities are associated with the intermittent pulmonary exacerbations that characterize CF. The long term objective of this project is to understand the microbiologic determinants of lung disease progression in CF in order to develop new strategies to improve the health of persons with CF.
The specific aims of this project are to (i) characterize the airway microbial and inflammatory changes that occur with pulmonary exacerbations, (ii) develop a model that predicts the occurrence of pulmonary exacerbations based on monitoring airway microbial communities and inflammation, and (iii) develop a dynamic model of CF host-microbiome interactions that will provide information about the mechanisms involved in infection-driven lung disease in CF. We have prospectively collected thousands of daily sputum samples from people with CF, many of whom experienced an exacerbation during the sputum collection period. We will use next-generation DNA sequencing and analysis of bacterial metabolites to characterize the structure and activity of the bacterial communities in samples obtained around the time of pulmonary exacerbations. We are especially interested in samples that were obtained in the days or weeks immediately preceding exacerbation onset. Our study will identify microbial community changes that correlate with exacerbation onset, severity and recovery. This information has great potential to enable the development of better approaches to preventing or treating exacerbations in CF. In summary, the work performed in this project will result in basic discoveries about the causes of lung disease in CF, enable the translation of these discoveries into clinical practice, and foster training and mentoring of emerging scientists and physicians.

Public Health Relevance

Respiratory failure is the cause of death in 95% of persons with cystic fibrosis (CF). Despite the prominent role that exacerbations of pulmonary illness play in the course of CF, our understanding of pulmonary exacerbation etiology and pathophysiology is remarkably limited. This project will use a unique collection of more than 10,000 CF sputum samples to characterize the dynamic structure and activity of the airway microbiome, particularly around the time of pulmonary exacerbations. In the short term, this study will identify targets of immediate translational clinical interest; in the longer term, we aim to elucidate the mechanisms underlying the microbial determinants of CF lung disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56HL126754-01A1
Application #
9336486
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Macgarvey, Nancy
Project Start
2016-09-15
Project End
2017-08-31
Budget Start
2016-09-15
Budget End
2017-08-31
Support Year
1
Fiscal Year
2016
Total Cost
$387,500
Indirect Cost
$137,500
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Carmody, Lisa A; Caverly, Lindsay J; Foster, Bridget K et al. (2018) Fluctuations in airway bacterial communities associated with clinical states and disease stages in cystic fibrosis. PLoS One 13:e0194060
Caverly, Lindsay J; LiPuma, John J (2018) Cystic fibrosis respiratory microbiota: unraveling complexity to inform clinical practice. Expert Rev Respir Med 12:857-865
Wandro, Stephen; Carmody, Lisa; Gallagher, Tara et al. (2017) Making It Last: Storage Time and Temperature Have Differential Impacts on Metabolite Profiles of Airway Samples from Cystic Fibrosis Patients. mSystems 2:
Quinn, Robert A; Whiteson, Katrine; Lim, Yan Wei et al. (2016) Ecological networking of cystic fibrosis lung infections. NPJ Biofilms Microbiomes 2:4