Shared metabolic pathway may drive CF lung infections, study finds

A metabolic pathway shared by lung cells and bacteria may help explain two major features of lung disease in people with cystic fibrosis (CF): the gradual thickening of the airways and persistent lung infections.

Researchers found that lab-grown human airway cells carrying disease-causing mutations increase their production of pyrimidines, molecules needed for cell growth, to compensate for problems with energy production. But this response inadvertently promotes excessive cell growth, potentially contributing to the thickening and narrowing of the airways seen in people with CF.

The same metabolic process also helps Pseudomonas aeruginosa (P. aeruginosa), a bacterium commonly involved in chronic lung infections in CF, adapt to the airway environment and multiply, potentially contributing to further changes in airway structure.

“Our findings identify pyrimidine metabolism as a central contributor [to] CF lung disease,” the researchers wrote, adding that pyrimidine signaling may represent a novel “tractable target.”

The study, “Host-pathogen pyrimidine metabolism drives cystic fibrosis lung disease,” was published in Nature Communications.

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Mucus buildup invites infections

CF is caused by mutations in the CFTR gene that impair the production or function of the CFTR protein, which regulates the movement of salt and water across cell surfaces. This leads to a buildup of thick, sticky mucus in the lungs, making it difficult to clear bacteria and contributing to repeated infections, often caused by P. aeruginosa.

Over time, the airway walls can thicken and become permanently narrowed, making breathing increasingly difficult. Excessive growth of cells lining the airways contributes to these changes, while persistent bacterial infections can further damage and reshape lung tissue by triggering inflammation. However, how these processes are connected remains poorly understood.

Researchers at Columbia University and collaborating institutions investigated whether changes in pyrimidine metabolism could help explain abnormal airway growth and persistent bacterial infections in CF. This pathway produces molecules needed to make DNA and RNA, which support cell growth, and is also involved in regulating inflammatory responses.

The researchers first examined bronchial epithelial cells, which line the main airways leading into the lungs, collected from people with and without CF. Cells from people with CF had higher levels of dihydroorotate dehydrogenase (DHODH), a key enzyme involved in pyrimidine production.

This appeared to drive excessive cell growth, as reducing DHODH production or blocking its activity markedly slowed the growth of airway cells from people with CF.

Further experiments in lab-grown human bronchial epithelial cells carrying CFTR mutations showed that this increased reliance on pyrimidine metabolism was a response to impaired mitochondrial function caused by defective CFTR. While helping the cells compensate, it also fueled excessive growth that may contribute to airway thickening and narrowing.

Supporting this connection, treatment with the CFTR modulator Trikafta (elexacaftor/tezacaftor/ivacaftor) reduced abnormal cell growth and brought levels of certain molecules involved in pyrimidine production closer to normal, linking changes in pyrimidine metabolism to CFTR dysfunction.

Yet blocking the pathway was not necessarily beneficial. When bronchial epithelial cells from people with and without CF were exposed to P. aeruginosa, DHODH activity helped limit the release of inflammatory molecules. In mice infected with the bacteria, blocking the enzyme increased inflammation and lung injury.

The researchers then turned to the bacteria themselves. They found that changes in the airway environment during infection appeared to favor P. aeruginosa strains that rely more heavily on pyrimidine metabolism, helping the bacteria adapt and persist in the lungs.

Analyses of bacteria collected from people with CF revealed increased expression of pyrD, a gene involved in pyrimidine production, particularly in strains adapted to long-term infection. In mice, an adapted P. aeruginosa strain reached much higher levels in the lungs than a closely related strain lacking pyrD, pointing to the pathway’s importance for bacterial growth.

Further experiments showed that pyrimidine metabolism helped the bacteria use nutrients such as glutamine to support growth and produce molecules needed to make alginate. This sticky substance forms a protective coating around bacterial communities, making them harder to eliminate and allowing infections to persist.

The pathway also appeared to influence how infected airways changed over time. In mice, adapted P. aeruginosa caused less inflammation and lung damage than a nonadapted strain while maintaining levels of a protein involved in tissue growth and remodeling, potentially helping sustain changes in airway structure.

The findings identify pyrimidine metabolism as “a unifying mechanism” linking abnormal airway growth and persistent P. aeruginosa infections in CF, the researchers wrote, suggesting it could represent a new therapeutic target.

However, they cautioned that “therapeutic targeting of this pathway, particularly in the context of infection, requires careful calibration.” Blocking the pathway may disrupt its protective effects against inflammation and worsen lung damage during infection, the researchers noted.

“Accordingly, a greater emphasis on bacterial pyrimidine targeting may represent a promising complement to CFTR modulators and antimicrobial therapies in the treatment of CF lung disease,” the team wrote.