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Sci Transl Med. 2019 Jul 3;11(499). pii: eaav4634. doi: 10.1126/scitranslmed.aav4634.

CFTR-PTEN-dependent mitochondrial metabolic dysfunction promotes Pseudomonas aeruginosa airway infection.

Author information

1
Department of Pediatrics, Columbia University, New York, NY 10032, USA.
2
Area de Microbiología Molecular, Centro de Investigación Biomédica de la Rioja (CIBIR), Microbiología Molecular, Logroño, LG 26006, Spain.
3
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania and Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
4
Section of Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
5
American Museum of Natural History, New York, NY 10024, USA.
6
Departamento de Diagnóstico Biomédico. Laboratorio de Microbiología, Hospital San Pedro, Logroño, LG 26006, Spain.
7
Department of Medicine, Columbia University, New York, NY 10032, USA.
8
Department of Pediatrics, Columbia University, New York, NY 10032, USA. asp7@columbia.edu.

Abstract

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor best known for regulating cell proliferation and metabolism. PTEN forms a complex with the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) at the plasma membrane, and this complex is known to be functionally impaired in CF. Here, we demonstrated that the combined effect of PTEN and CFTR dysfunction stimulates mitochondrial activity, resulting in excessive release of succinate and reactive oxygen species. This environment promoted the colonization of the airway by Pseudomonas aeruginosa, bacteria that preferentially metabolize succinate, and stimulated an anti-inflammatory host response dominated by immune-responsive gene 1 (IRG1) and itaconate. The recruitment of myeloid cells induced by these strains was inefficient in clearing the infection and increased numbers of phagocytes accumulated under CFTR-PTEN axis dysfunction. This central metabolic defect in mitochondrial function due to impaired PTEN activity contributes to P. aeruginosa infection in CF.

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