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Expanding the Research Horizons
Flagellin Proven to Stimulate Chloride Channel

“Noone has ever looked into its relation to the underlying chloride ion channel defect in cystic fibrosis before, or thought about studying what bacteria actually do to the Chloride response in epithelial cells.”

As part of a joint collaboration with Terry E. Machen, PhD, at the Department of Molecular and Cell Biology at the University of California, Berkeley, CHORI investigator Beate Illek, PhD and her lab report in the July issue of the American Journal of Physiology, Lung Cell Molecular Physiology that flagellin, a protein found in flagellated and motile bacteria, stimulates Chloride secretion as part of the body’s innate immune system response.

“Infection with the opportunistic pathogen Pseudomonas aeruginosa causes severe life-threatening airway infections that are a frequent cause for hospitalization of cystic fibrosis patients,” explains Dr. Illek.

Cystic fibrosis (CF) is a debilitating disease caused by a mutation in the gene that encodes for the protein, cystic fibrosis transmembrane conductance regular (CFTR). Because of this mutation, the CFTR protein doesn’t function properly, and patients suffering from CF experience significant loss in quality of life and lifespan.

While great research gains in CF have been made, now extending patients’ average life spans from the early 20’s to the late 30’s, the search is still on for a cure or ameliorative treatment.

“We would like to find the magic bullet that treats the inflammation and in addition has a stimulatory effect on CFTR activity,” says Dr. Illek. “To do that, we are trying to understand how the CFTR protein is regulated, and what other pathways might exist that could be targeted.”

The main responsibility of the CFTR protein is to conduct Chloride and Bicarbonate ions from one side of the epithelial cells that line the airway passages tothe other side of those cells, which in turn, triggers the flow of fluid or water across the cells and into the nasal passages. In patients with CF, the CFTR mutation prevents this Chloride channel from properly functioning.
“Healthy lungs are able to respond to bacterial toxins by secreting chloride and fluid in order to flush the bacteria out,” explains Dr. Illek. “Because the Chloride channel is defective in CF patients, they can’t flush it out.”
Instead, the lungs and airways of CF patients develop a build-up of sticky mucus that is highly prone to bacterial infection. Dr. Illek and her colleagues wanted to investigate whether or not flagellin, which is released during bacterial infections, could trigger a Chloride response in epithelial cells.

“The most significant finding is that flagellin does in fact activate and stimulate the CFTR channel to conduct Chloride ions,” says Dr. Illek.

Most research that has been done on the CFTR protein has focused on classical pathways that stimulate the chloride channel, but Dr. Illek’s latest results suggest that other pathways exist that could prove to be alternative targets for potential drug development.

“What we’ve done is to expand the research into more biological targets by looking at how they interact with the CFTR channel, and what other ways we might get at to trigger the chloride response,” Dr. Illek explains.
This isn’t the first time Dr. Illek has discovered an alternative pathway for CFTR regulation, as Dr. Illek and her CHORI colleagues were also the first to report that Vitamin C could impact the Chloride channel. Now, Dr. Illek has added one more alternative target to the list.

“There has been a lot of research conducted on the classical pathways for the stimulation of the Chloride channel,” says Dr. Illek, “but this is the first time it’s been shown that bacterial products also target the CFTR channel.”


Tuesday, May 17, 2011 8:19 AM

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