Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

In cystic fibrosis, lungs feed deadly bacteria

22.08.2019

In cystic fibrosis, Pseudomonas aeruginosa is a much-feared pathogen. The bacterium easily colonizes the lungs of people with cystic fibrosis, leading to chronic infections that are almost impossible to eradicate and are ultimately fatal.

Why does P. aeruginosa, but not other common bacteria, thrive in cystic fibrosis lungs?


P. aeruginosa bacteria (blue) thrive in lungs that produce lots of succinate, a preferred food.

Credit: Sebastián Riquelme, Columbia University Irving Medical Center

A new study from researchers at Columbia University Vagelos College of Physicians and Surgeons suggests the answer has to do with the bacterium's culinary preference for succinate, a byproduct of cellular metabolism, that is abundant in cystic fibrosis lungs.

"Preventing infection by P. aeruginosa could greatly improve the health of people with cystic fibrosis," says Sebastián A. Riquelme, PhD, the study's lead author and a postdoctoral fellow in the Department of Pediatrics. "And it's possible that we could control infection by targeting the bacteria's use of succinate in the lung."

Excess Succinate in CF Lungs

The excess succinate in the lungs of people with cystic fibrosis comes from an interaction between two proteins, CFTR and PTEN. Mutations in the CFTR gene causes cystic fibrosis by preventing the CFTR protein from transporting ions in and out of cells. But the mutations also disrupt CFTR's interactions with PTEN (a discovery made by the Columbia team in 2017).

It is this abnormal PTEN-CFTR interaction, the new study found, that causes lung cells to release an excessive amount of succinate. The succinate fueled growth of P. aeruginosa in the lungs of mice, but had no effect on Staphylococcus aureus, another major pathogen.

More Succinate, More Slime

Not only does P. aeruginosa thrive in a succinate-rich environment, it actively adapts to the abundance of its favored food.

"Succinate-adapted bacteria divert their metabolism into the production of extracellular slime that makes the organisms extremely difficult to eradicate from the lung," says the study's senior author Alice Prince, MD, the John M. Driscoll Jr., MD and Yvonne Driscoll, MD Professor of Pediatrics. "These bacteria are the cause of chronic infection in cystic fibrosis."

The succinate-fed bacteria also suppress the immune response, furthering hampering the body's ability to control the infection.

Targeting Succinate

The new findings--made in mice and in human cells in tissue culture--suggest that it may be possible to treat P. aeruginosa infection by restoring the interaction between PTEN and CFTR, even if CFTR's other functions are impaired.

New drugs for cystic fibrosis, such as the lumacaftor and ivacaftor combination currently available, restore the CFTR-PTEN interaction and may decrease the generation of succinate.

Limiting the accumulation of succinate may also reduce bacterial growth and adaptation. Succinate is mainly produced by immune cells during the inflammatory response, Riquelme says. "We predict that by controlling the exaggerated inflammation observed in the airway, we could reduce succinate and P. aeruginosa infection."

###

The study, "CFTR-PTEN-dependent mitochondrial metabolic dysfunction promotes Pseudomonas aeruginosa airway infection," was published in July in Science Translational Medicine.

Additional authors: Carmen Lozano (Centro de Investigación Biomédica de la Rioja, Microbiología Molecular, Logroño, Spain), Ahmed M. Moustafa (University of Pennsylvania and Children's Hospital of Philadelphia), Kalle Liimatta (Columbia University Irving Medical Center), Kira L. Tomlinson (CUIMC), Clemente J. Britto (Yale University School of Medicine), Sara Khanal (Yale University School of Medicine), Simren K. Gill (CUIMC), Apurva Narechania (American Museum of Natural History, New York, NY), José M. Azcona-Gutiérrez (Hospital San Pedro, Logroño, Spain), Emily DiMango (CUIMC), Yolanda Saénz (Centro de Investigación Biomédica de la Rioja, Microbiología Molecular), and Paul J. Planet (University of Pennsylvania and Children's Hospital of Philadelphia).

The study was supported by the National Institutes of Health (grants R35HL135800, GG011557-26 to Columbia University Irving Institute for Clinical and Translational Research, UL1TR001873, and S10RR027050); the Cystic Fibrosis Foundation (pilot grant PLANET16I and postdoctoral fellowship RIQUEL 17F0/PG008837); an S.B. postdoctoral contract (CD15/00125); an M-AES mobility grant (MV16/00053); Pediatric Infectious Diseases Society (St. Jude Award), Thrasher Research Fund (PG005871), Doris Duke Clinical Scientist Development Award (2012060), and a Louis V. Gerstner Scholar Award.

The authors declare that they have no competing interests.

The Department of Pediatrics at Columbia University Vagelos College of Physicians and Surgeons is a top ranked department nationally, with more than $20 million per year in research funding from the National Institutes of Health, and is the only pediatrics department in New York ranked in the top 25 by US News & World Report.

Lucky Tran | EurekAlert!
Further information:
https://www.cuimc.columbia.edu/news/cystic-fibrosis-lungs-feed-deadly-bacteria

Further reports about: CFTR Metabolism PTEN aeruginosa bacteria cystic fibrosis fibrosis lungs

More articles from Life Sciences:

nachricht Turning carbon dioxide into liquid fuel
06.08.2020 | DOE/Argonne National Laboratory

nachricht Tellurium makes the difference
06.08.2020 | Friedrich-Schiller-Universität Jena

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: ScanCut project completed: laser cutting enables more intricate plug connector designs

Scientists at the Fraunhofer Institute for Laser Technology ILT have come up with a striking new addition to contact stamping technologies in the ERDF research project ScanCut. In collaboration with industry partners from North Rhine-Westphalia, the Aachen-based team of researchers developed a hybrid manufacturing process for the laser cutting of thin-walled metal strips. This new process makes it possible to fabricate even the tiniest details of contact parts in an eco-friendly, high-precision and efficient manner.

Plug connectors are tiny and, at first glance, unremarkable – yet modern vehicles would be unable to function without them. Several thousand plug connectors...

Im Focus: New Strategy Against Osteoporosis

An international research team has found a new approach that may be able to reduce bone loss in osteoporosis and maintain bone health.

Osteoporosis is the most common age-related bone disease which affects hundreds of millions of individuals worldwide. It is estimated that one in three women...

Im Focus: AI & single-cell genomics

New software predicts cell fate

Traditional single-cell sequencing methods help to reveal insights about cellular differences and functions - but they do this with static snapshots only...

Im Focus: TU Graz Researchers synthesize nanoparticles tailored for special applications

“Core-shell” clusters pave the way for new efficient nanomaterials that make catalysts, magnetic and laser sensors or measuring devices for detecting electromagnetic radiation more efficient.

Whether in innovative high-tech materials, more powerful computer chips, pharmaceuticals or in the field of renewable energies, nanoparticles – smallest...

Im Focus: Tailored light inspired by nature

An international research team with Prof. Cornelia Denz from the Institute of Applied Physics at the University of Münster develop for the first time light fields using caustics that do not change during propagation. With the new method, the physicists cleverly exploit light structures that can be seen in rainbows or when light is transmitted through drinking glasses.

Modern applications as high resolution microsopy or micro- or nanoscale material processing require customized laser beams that do not change during...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

“Conference on Laser Polishing – LaP 2020”: The final touches for surfaces

23.07.2020 | Event News

Conference radar for cybersecurity

21.07.2020 | Event News

Contact Tracing Apps against COVID-19: German National Academy Leopoldina hosts international virtual panel discussion

07.07.2020 | Event News

 
Latest News

Rare Earth Elements in Norwegian Fjords?

06.08.2020 | Earth Sciences

Anode material for safe batteries with a long cycle life

06.08.2020 | Power and Electrical Engineering

Turning carbon dioxide into liquid fuel

06.08.2020 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>