Cystic Fibrosis (CF) is a genetic disease that dramatically decreases life expectancy and quality. The disease is characterized by polymicrobial infections, which lead to lung remodeling and airway mucus plugging. CF patients experience intermittent exacerbations that cause airway scarring and eventually result in seriously impaired respiration. Despite aggressive therapy, most CF patients will die from respiratory failure caused by the chronic lung infections. Standard clinical microbiological studies and antibiotic susceptibility testing have severe limitations in predicting medical outcomes from specific therapies. This is due in part because the dynamics of microbes and their viral predators (phage) are essentially unknown in the CF lung. The goal of this study is to use metagenomics and microscopy to characterize these two communities and determine how they change in response to perturbations such as disease severity, antibiotic treatments, and chemical treatments designed to break up the mucus plugs. The metagenomic data will be used to determine how the types and metabolic functions of both the viral and microbial communities change. Microbial growth rates and phage-mediated death will also be measured. To better understand the spatial dynamics of the microbial and viral communities, we will also be dissecting lungs of CF patients. Viral and microbial metagenomes from individual lobes will be sequenced. To determine where specific species of microbes reside in the mucus plugs, fluorescent in situ hybridization with 16S rDNA probes will used on tissue samples. Together these data sets will be used to parameterize three complementary ecological models of the CF lung. Then these models will be used as in silico tests of alternative treatment regimes (e.g., adjust timing of antibiotic administration). When completed, we will have generated an unprecedented view of the viral and microbial communities in CF and how they respond to treatments. With the models, we will be able to better understand the dynamics of these communities and test alternative treatment regimes to prolong and improve the lives of CF patients.

Public Health Relevance

It is increasingly recognized that ecological approaches can help control infectious diseases and promote human health. The goal of this proposal is to use microbial ecology methods to better understand and control the devastating disease Cystic Fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM095384-02
Application #
8197889
Study Section
Special Emphasis Panel (ZGM1-GDB-2 (MC))
Program Officer
Singh, Shiva P
Project Start
2010-12-01
Project End
2014-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$475,153
Indirect Cost
$149,233
Name
San Diego State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
073371346
City
San Diego
State
CA
Country
United States
Zip Code
92182
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Whiteson, Katrine L; Meinardi, Simone; Lim, Yan Wei et al. (2014) Breath gas metabolites and bacterial metagenomes from cystic fibrosis airways indicate active pH neutral 2,3-butanedione fermentation. ISME J 8:1247-58
Quinn, Robert A; Alexandrov, Theodore (2014) The community ecology of microbial molecules. J Chem Ecol 40:1161-2
Quinn, Robert A; Lim, Yan Wei; Maughan, Heather et al. (2014) Biogeochemical forces shape the composition and physiology of polymicrobial communities in the cystic fibrosis lung. MBio 5:e00956-13
Whiteson, Katrine L; Hernandez, David; Lazarevic, Vladimir et al. (2014) A genomic perspective on a new bacterial genus and species from the Alcaligenaceae family, Basilea psittacipulmonis. BMC Genomics 15:169
Lim, Yan Wei; Schmieder, Robert; Haynes, Matthew et al. (2013) Mechanistic model of Rothia mucilaginosa adaptation toward persistence in the CF lung, based on a genome reconstructed from metagenomic data. PLoS One 8:e64285
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