Analysis: New cystic fibrosis clue found?

BOSTON, July 6 (UPI) -- A lung protein has been found to play a key role in immunity and may be another clue as to why cystic fibrosis patients are so susceptible to chronic, debilitating infections, researchers say.

The protein, MVP, works in concert with another immune mechanism previously identified to be defective in cystic fibrosis patients.

Cystic fibrosis is an inherited disease that affects the lungs and pancreas, and causes an excessive buildup of mucous. The thick mucous makes it difficult for the lungs to function normally and provides an environment for bacteria, primarily pseudomonas aeruginosa, to flourish.

Pseudomonas is a common bacteria that healthy people fight off easily but is the cause of constant bouts of debilitating infection in people with cystic fibrosis, said Gerald B. Pier, a professor at Harvard Medical School whose research appears in the July 6 issue of Science.

"Were trying to understand why it is that cystic fibrosis patients get infected with this one microbe so frequently. There is no other situation in human medicine where a genetic defect is so closely associated with infection by just one type of microbe," Pier told United Press International.

Scientists haven't understood how the immune system is activated against pseudomonas, and that is what the Pier team set out to do.

"Our results are important in that we can use this unusual medical situation to understand how the lung in general handles microbial infection," Pier said.

According to Pier, pseudomonas try to gain entry through the epithelial cells that line the lungs by binding to a protein on the cell membrane called CFTR. In a normal lung, this action alerts the body that a bacterium is trying to invade, and the body marshals a strong immune response to fend it off.

Pier found that when the pseudomonas bind to CFTR, it triggers the production of another set of proteins, called major vault protein. These vault proteins gather on the cell membrane to help fight off the pseudomonas.

People with cystic fibrosis have defective CFTRs, so they aren't able to mount an immune response quickly enough and with enough strength, Pier said.

Pier said the vault proteins are an important co-factor that works with the CFTR to clear the lungs of infection.

More research would need to be done to determine if the vault protein step also is defective in people with cystic fibrosis, Pier said.

"We'd be interested in whether there is variation in the genes that code for major vault proteins that may be associated with better outcomes," Pier said.

"Healthy people make the right, correct early response and get rid of the bug. But if you have cystic fibrosis that response is delayed, probably by hours, that gives the organism time to set up in the lungs of a cystic fibrosis patient and avoid clearance by the immune system. It survives within the mucus.

"In cystic fibrosis, the CFTR protein is very important to alerting the body to the infection. They don't have a functioning CFTR, so they can't alert the body in a timely fashion.

The CFTRs have many functions and primarily regulate how much salt moves in and out of cells, Michael Konstan, director of the Cystic Fibrosis Center at Case Western Reserve University, told UPI.

The failure to regulate salt across cells in cystic fibrosis patients leads to excessive mucus buildup in the lungs, Konstan said.

Cystic fibrosis is caused by mutations in the CFTR gene. It is most common in white people of European heritage, and in this group the defective gene is carried by one in 29 people. A child must inherit a copy of the gene from each parent in order to have cystic fibrosis.

Babies with cystic fibrosis get infected with pseudomonas by age 3. By 10 in many people the infection is chronic, and most people with cystic fibrosis do not live into their 40s.

Treatments available involve antibiotics and physically removing the mucous from the lungs.

In addition to conducting basic research to understand how lung immunity works, Pier's lab is trying to develop vaccines to thin lung mucous in cystic fibrosis patients and to fight infection.

Nam Soo Joo, a research associate with the Cystic Fibrosis Research Laboratory at Stanford University, said the CFTR gene mutations were discovered in 1989. Since then, scientists have found more than 1,000 different mutations to the gene.

"In some cystic fibrosis patients the symptoms are very severe and in other people the symptoms are light, depending on the mutation," he said.

Diana Wetmore, with the research funding arm of the Cystic Fibrosis Foundation, said a number of vaccines are under development to help treat cystic fibrosis.

"In terms of therapies we are helping promote, we are looking to make progress with anti-inflammatory drugs and anti-infective drugs. We are also interested in mucous regulation and how nutritional status impacts patients to resist lung infection," Wetmore told UPI.

This year the foundation will fund more than $100 million in research, she said.

"We're also interested in determining how the immune system of a healthy lung manages to keep lungs sterile and why people with cystic fibrosis have difficulty keeping their lungs sterile," Wetmore said.