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The Microbiota of the Pediatric CF Airway: What Role Does It Play?
Progressive, obstructive lung disease remains the biggest cause of morbidity and early mortality in cystic fibrosis (CF). Early detection and treatment of pulmonary decline is key to optimal long-term outcome; however, physiologic measures of lung function and radiologic outcomes fail to capture the inflammation and infection that begin in infancy, which are often asymptomatic.
Mucus stasis and impaired bacterial killing provide the optimal environment for chronic bacterial infection in the CF airway. Culture-independent approaches using next-generation sequencing techniques have revealed a more complex, polymicrobial community in the CF airway than previously identified using traditional culture. Interestingly, a large number of these communities are anaerobes, known to inhabit the oral cavity and thought to be non-pathogenic. Recently, anaerobes in CF sputum were found to generate a nutritional environment through fermentative metabolism and mucin degradation that facilitates the growth and persistence of bacterial pathogens like Pseudomonas aeruginosa, a known contributor to lung function decline in CF.
Surprisingly, Dr. Laguna has found that anaerobes are already present in higher relative abundance compared to traditional CF pathogens in the lower airways of infants with CF; however, we do not yet understand their contribution in the development of early lung disease. The key question remains whether the early presence of anaerobic bacteria in the lower airways of CF infants predisposes them to a more rapid decline in lung function, more frequent pulmonary exacerbations or structural lung damage.
Therefore, the central hypothesis of this proposal is that anaerobic bacteria in the lower airways of infants and children with CF is associated with fermentative metabolism and will have a unique metabolic and metaproteomic biosignature that incites inflammation and contributes to the development of early CF lung disease. This research takes advantage of the team’s expertise and established collaborations with experts in the field as well as a unique and valuable resource: a collection of bronchoalveolar lavage fluid (BALF) samples from children with/without CF available for immediate analysis.
The aims of this project are three-fold:
- First, through the measurement of fermentation and mucin products, to determine if anaerobic communities in BALF associate with a fermentative environment in the CF airway.
- Second, to determine if the lower airway microbiota is associated with the metabolomic profile measured in BALF from young children with/without CF.
- Third, through innovative metaproteomics technology, to characterize the metaproteome to determine the metabolic activity of the microbial communities in the CF airway.
The knowledge gained upon completion of this project would allow healthcare providers to consider anaerobic specific antibiotics or encourage the development of new antimicrobials targeting bacterial fermentative processes as a new treatment for CF lung disease.
Specimen Collection in Pediatric Subjects (SPINS)
Cystic fibrosis (CF) is a life-shortening, recessive genetic disorder affecting approximately 30,000 people in the United States. It impacts all races and ethnicities. It is characterized by pulmonary infection, chronic inflammation, pulmonary exacerbations, decline in lung function and poor nutritional status.
According to the 2022 Cystic Fibrosis Patient Registry annual report, the median predicted age of survival is now into the early 50s. While this shows significant improvement from previous years, there is still progress to be made. Even with the approval of new CFTR modulator therapy that has had dramatic impact on clinical outcomes, infection and inflammation in the lungs remains a significant problem. Additionally, ~20% of people with CF either do not qualify for a CFTR modulator medication or do not tolerate it.
With the support of the Cystic Fibrosis Foundation, basic and translational scientists are exploring the etiology and cellular mechanisms involved in CF to identify new molecular therapeutic targets. Clinical researchers are collaborating with commercial biotechnical firms to develop new therapeutic agents aimed at the amelioration and possible cure of the disease.
Access to banked, valuable clinical samples to facilitate the work is key in this rare disease. The SPINS project aims to collect oropharyngeal swabs, sputum, bronchoalveolar lavage fluid, blood and urine to serve as the foundation for current and future research projects in rare lung disease.
First Detect Then Destroy: Fungi in the CF Airway (FUN)
Although significant progress has been made in the approach to cystic fibrosis (CF) lung disease with the development of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, infection and inflammation remain problematic.
The CF scientific community has made great strides in understanding the polymicrobial and dynamic nature of the bacterial communities in the CF airway through the application of next generation sequencing (NGS) techniques; however, CF lung disease is triggered by more than just bacteria. My research team is well-positioned to contribute to the investigation of the fungal communities within the CF airway through the intensive study of a newly developed (and published) NGS technique to determine which airway samples can be used to detect fungi.
Using banked and prospectively collected oropharyngeal (OP) swabs, sputum and bronchoalveolar lavage fluid (BALF) samples, we will leverage the expertise of our longstanding national collaborators at the Cystic Fibrosis Microbiome Analysis Core (CFMAC) at the University of Colorado and an established expert in fungal disease in CF at the University of Pennsylvania to move the field forward. Our work will have the following objectives:
- Compare fungal detection between culture and NGS in the upper and lower airway to better understand the strengths and weaknesses of NGS compared to standard clinical culture methods.
- Describe differences in fungal communities detected by airway sample type (OP swab, sputum and BALF) (this is key in the era of CFTR modulators and decreased availability of expectorated sputum).
- Develop a cohort that can be followed longitudinally for further study of fungi and clinical outcomes.