BETHESDA, MD (NIH) -- Cystic fibrosis (CF) is a fatal lung disease caused by an altered gene, but how the gene affects cells is not completely understood. Now, researchers have new evidence suggesting the gene can change the internal chemistry of some lung cells, making them more susceptible to certain bacteria that cause sickness and, ultimately, death. The investigators also used a simple process to correct those changes in the test tube. The study appears in the Proceedings of the National Academy of Sciences online early edition.

"This research proposes a novel explanation for why lung infections are so persistent in cystic fibrosis," says Christopher Taylor, Sc.D., an expert on bacterial respiratory diseases with the National Institute of Allergy and Infectious Diseases (NIAID), which funded the study. "If additional studies support the findings presented here, we will have a better understanding of the disease and perhaps new ways to treat it."

People with CF battle chronic respiratory infections and have difficulty breathing because of mucus accumulation in the lungs. Most patients ultimately die from a buildup of Pseudomonas aeruginosa, a common bacterium that rarely causes disease in healthy individuals.

Although the CF gene has been known since 1989, exactly how it is linked to increased susceptibility to P. aeruginosa and other bacteria is unknown. The gene encodes a protein called CFTR, which regulates the flow of charged atoms, or ions, into and out of cells. Maintaining a proper ion balance is critical for cells to function properly, but researchers have not known how an imbalance makes the lung cells a more attractive site for bacteria to grow.

To solve that riddle, Jens Poschet, Ph.D., and Vojo Deretic, Ph.D., began to study the link between CFTR and bacterial infections while both researchers were at the University of Michigan; they are now at the University of New Mexico. Because bacteria must adhere to proteins on the cell surface before they can invade, the researchers wondered if a malfunctioning CFTR could lead to changes in those surface proteins. If so, perhaps the cell surface would become more amenable to invading bacteria.

Drs. Deretic and Poschet first looked inside cells, where all proteins are made and then transported to a series of internal compartments for final processing. Some of those compartments form the trans-Golgi network, a type of central packaging center that sorts proteins and gives them their finishing touches. Among those touches, specific enzymes attach small sugar molecules to many surface proteins. The sugars serve as molecular flags that help the proteins recognize other cells or chemical signals.

When the researchers studied the trans-Golgi network in cells with an altered CFTR, they found the compartments were more acidic than normal and failed to attach the appropriate sugar molecules to the proteins bound for the cell surface. "The sugar-adding enzymes only work in a specific pH range. The altered CFTR appears to throw off the ion balance in the cells, messing up the pH," explains Dr. Deretic.

Without the sugars on the cell surface, P. aeruginosa and other bacteria stuck to the cells much more readily, suggesting a clear link between the CFTR gene and increased susceptibility to respiratory infections. When the investigators treated the cells in a test tube by restoring normal acidity, the bacteria no longer could adhere. "This was an exciting discovery to us, because in the test tube at least we can correct the deficiency with simple maneuvers," says Dr. Deretic.

If their findings hold true in people as well, Dr. Deretic sees the potential for a new approach to treatment. "We already have ion pump inhibitors and antacids for treating heartburn," he says. "If we can design similar compounds to go to the lungs, we might have a simple solution to greatly improve the health of CF patients."

NIAID is a component of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, tuberculosis, malaria, autoimmune disorders, asthma and allergies.