Chronic airway infections with Pseudomonas aeruginosa claim the lives of the vast majority of cystic fibrosis (CF) patients. Once infection is established patients suffer frequent disease flares known as pulmonary exacerbations. During exacerbations, increased lung inflammation and injury produce worsening pulmonary function, and marked respiratory and systemic symptoms. While some flares produce transient illness, one out of four causes permanent lung function decline. The cumulative effect of these events produce respiratory failure and death, typically in the third decade of life. Unfortunately, the mechanisms that produce exacerbations remain unknown, and new treatments have been difficult to develop. Here we exploit the infrastructure of an ongoing clinical trial, and new findings about genetic diversity within infecting P. aeruginosa populations as tools to study exacerbation mechanisms. Most CF infections are clonal, meaning that the infecting population is composed of the progeny of a single isolate. In preliminary studies, we found that infecting P. aeruginosa strains evolve to produce genetically diverse (but clonally-related) bacterial populations within the host. Furthermore, evolved bacterial subpopulations differ in traits known to affect host inflammatory and injury responses. The presence of subpopulations that elicit markedly different host responses could have a major effect on disease manifestations, as our preliminary data shows that flares are associated with marked changes in infecting population composition. We will build on these findings to test the hypothesis that at the onset of exacerbations, changes in the composition of infecting P. aeruginosa populations elicit host responses leading to lung inflammation and injury. The parent clinical trial presents an unusual opportunity to test this hypothesis in human subjects.

Public Health Relevance

CF is the most common lethal inherited disease of Caucasians and chronic P. aeruginosa airway infections claim the lives of most patients. Once established, infection is permanent and lung function steadily declines. Disease flares known as exacerbations are among the most important problems in CF. Exacerbations occur frequently and cause reduced lung function, breathlessness, severe cough, and anorexia. The annual number of exacerbations correlates with rates of lung function decline, poor quality of life, the incidence of CF-related diabetes, and lower 2 and 5 yr survival rates. This study tests the hypothesis that at the onset of cystic fibrosis (CF) exacerbations, changes in infecting population composition produce lung inflammation or injury. To test this, we will measure changes in the abundance of variant isolates during flares and determine how changes affect host responses. We will also use proteomics to determine how exacerbation-associated variants differ in functioning. Finally, we will attempt to link specific bacterial proteins and pathways to exacerbation-related host responses. This work could find new explanations for disease flares and lead to new treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL110879-01
Application #
8214963
Study Section
Special Emphasis Panel (ZHL1-CSR-G (M1))
Program Officer
Banks-Schlegel, Susan P
Project Start
2011-09-01
Project End
2015-05-31
Budget Start
2011-09-01
Budget End
2012-05-31
Support Year
1
Fiscal Year
2011
Total Cost
$404,861
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Schweppe, Devin K; Chavez, Juan D; Lee, Chi Fung et al. (2017) Mitochondrial protein interactome elucidated by chemical cross-linking mass spectrometry. Proc Natl Acad Sci U S A 114:1732-1737
Chavez, Juan D; Schweppe, Devin K; Eng, Jimmy K et al. (2016) In Vivo Conformational Dynamics of Hsp90 and Its Interactors. Cell Chem Biol 23:716-26
Schweppe, Devin K; Chavez, Juan D; Navare, Arti T et al. (2016) Spectral Library Searching To Identify Cross-Linked Peptides. J Proteome Res 15:1725-31
Schweppe, Devin K; Chavez, Juan D; Bruce, James E (2016) XLmap: an R package to visualize and score protein structure models based on sites of protein cross-linking. Bioinformatics 32:306-8
Chavez, Juan D; Eng, Jimmy K; Schweppe, Devin K et al. (2016) A General Method for Targeted Quantitative Cross-Linking Mass Spectrometry. PLoS One 11:e0167547
Schweppe, Devin K; Zheng, Chunxiang; Chavez, Juan D et al. (2016) XLinkDB 2.0: integrated, large-scale structural analysis of protein crosslinking data. Bioinformatics 32:2716-8
Adam, Ryan J; Hisert, Katherine B; Dodd, Jonathan D et al. (2016) Acute administration of ivacaftor to people with cystic fibrosis and aG551D-CFTRmutation reveals smooth muscle abnormalities. JCI Insight 1:e86183
Wu, Xia; Chavez, Juan D; Schweppe, Devin K et al. (2016) In vivo protein interaction network analysis reveals porin-localized antibiotic inactivation in Acinetobacter baumannii strain AB5075. Nat Commun 7:13414
Wu, Xia; Held, Kiara; Zheng, Chunxiang et al. (2015) Dynamic Proteome Response of Pseudomonas aeruginosa to Tobramycin Antibiotic Treatment. Mol Cell Proteomics 14:2126-37
Jorth, Peter; Staudinger, Benjamin J; Wu, Xia et al. (2015) Regional Isolation Drives Bacterial Diversification within Cystic Fibrosis Lungs. Cell Host Microbe 18:307-19

Showing the most recent 10 out of 19 publications