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Peer-reviewedCC BY-NC-NDNature communications

Host-pathogen pyrimidine metabolism drives cystic fibrosis lung disease.

  • Gaurav Kumar Lohia1
  • Ying-Tsun Chen1
  • Samantha Chen1
  • Ayesha Beg1
  • Erin Theiller2
  • Aomeng Cui3,4
  • Ahmed M Moustafa2
  • Sebastián A Riquelme5
5 affiliations
  1. 1Division of Infectious Diseases, Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
  2. 2Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Center for Microbial Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  3. 3Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
  4. 4Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
  5. 5Division of Infectious Diseases, Department of Pediatrics, Columbia University Medical Center, New York, NY, USA. [email protected].
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Abstract

Cystic fibrosis (CF), caused by CFTR mutations, is characterized by progressive pulmonary remodeling, particularly during bacterial infection. This pathological environment, exacerbated by altered epithelial growth, leads to thickened airway walls, inducing permanent narrowing and long-term breathing difficulties. However, what drives this adverse milieu remains unclear. Here, we identify activation of the de novo pathway of pyrimidine synthesis (DNPPS) as a central contributor of CF lung remodeling. In response to impaired mitochondrial bioenergetics, CFTR-mutant epithelial cells engage compensatory DNPPS activity, functionally coupling mitochondrial oxidative metabolism to pyrimidine production and, inadvertently, promoting proliferation. This phenotype is reversible with CFTR modulators and pharmacologic DNPPS inhibitors using clinically established agents. Strikingly, Pseudomonas aeruginosa, the predominant CF pathogen, undergoes convergent pyrimidine adaptation, activating its own DNPPS machinery to amplify biomass and sustain a remodeled niche. Together, these findings define pyrimidine metabolism as a shared host-pathogen axis driving epithelial restructuring and bacterial persistence in the CF lung.

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Cite

BibTeXRIS
BibTeX
@article{lohia2026hostpathogen,
  title = {{Host-pathogen pyrimidine metabolism drives cystic fibrosis lung disease.}},
  author = {Gaurav Kumar Lohia and Ying-Tsun Chen and Samantha Chen and Ayesha Beg and Erin Theiller and Aomeng Cui and Ahmed M Moustafa and Sebastián A Riquelme},
  journal = {Nature communications},
  year = {2026},
  month = sep,
  doi = {10.1038/s41467-026-77940-z},
  url = {https://europepmc.org/article/MED/42907429},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Host-pathogen pyrimidine metabolism drives cystic fibrosis lung disease.
AU  - Gaurav Kumar Lohia
AU  - Ying-Tsun Chen
AU  - Samantha Chen
AU  - Ayesha Beg
AU  - Erin Theiller
AU  - Aomeng Cui
AU  - Ahmed M Moustafa
AU  - Sebastián A Riquelme
PY  - 2026
DA  - 2026/09/22
JO  - Nature communications
DO  - 10.1038/s41467-026-77940-z
UR  - https://europepmc.org/article/MED/42907429
AB  - Cystic fibrosis (CF), caused by CFTR mutations, is characterized by progressive pulmonary remodeling, particularly during bacterial infection. This pathological environment, exacerbated by altered epithelial growth, leads to thickened airway walls, inducing permanent narrowing and long-term breathing difficulties. However, what drives this adverse milieu remains unclear. Here, we identify activation of the de novo pathway of pyrimidine synthesis (DNPPS) as a central contributor of CF lung remodeling. In response to impaired mitochondrial bioenergetics, CFTR-mutant epithelial cells engage compensatory DNPPS activity, functionally coupling mitochondrial oxidative metabolism to pyrimidine production and, inadvertently, promoting proliferation. This phenotype is reversible with CFTR modulators and pharmacologic DNPPS inhibitors using clinically established agents. Strikingly, Pseudomonas aeruginosa, the predominant CF pathogen, undergoes convergent pyrimidine adaptation, activating its own DNPPS machinery to amplify biomass and sustain a remodeled niche. Together, these findings define pyrimidine metabolism as a shared host-pathogen axis driving epithelial restructuring and bacterial persistence in the CF lung.
SN  - 2041-1723
ER  -