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Advances in Understanding and Combating Cystic Fibrosis Lung Infections

Individuals with cystic fibrosis (CF) typically develop chronic, progressively debilitating, and sometimes lethal Pseudomonas aeruginosa infections of the lungs. However, two recent reports from University of Iowa (UI) researchers confirm that those infections involve biofilms and thus suggest new ways of overcoming them. The first explains how biofilm formation plays a major role in the persistence of P. aeruginosa CF lung infections, and the second describes how the simple sugar xylitol may enhance natural defenses to combat such infections.

Clues suggesting that P. aeruginosa cells form biofilms in the lungs of CF patients are plentiful, according to E. Peter Greenberg, UI professor of microbiology and principal author of a report in the 12 October issue of Nature that helps to prove the point. Among those clues, he notes, are "the high level of antibiotic resistance" and a host immune response that "does more harm than good." Both those properties are "hallmarks" of a bacterial biofilm.

Confirmation hinged on Greenberg's earlier identification of two quorum-sensing molecules, one longer than the other, that control expression of dozens of P. aeruginosa genes. Using a radioactive precursor, he and his collaborators developed a means for measuring how rapidly these specific quorum-sensing molecules are synthesized. According to this test, free-floating P. aeruginosa cells produce up to 10 times more of the longer molecule than of the shorter. However, the situation is reversed for P. aeruginosa recovered from CF sputum samples, which yield up to 10 times as much of the shorter molecule. But, when those bacteria grow in broth, they produce mainly the longer molecule.

The results indicate that "most of the P. aeruginosa in the lung are in the biofilm state," says Greenberg, confirming biofilm studies of nearly two decades ago by Bill Costerton, then at the University of Calgary and now director of the Center for Biofilm Engineering at the University of Montana in Bozeman. Costerton, who calls Greenberg's findings "fabulous," and his colleagues earlier observed slime-enmeshed bacterial aggregates typical of biofilms in sputum samples from CF patients.

"The fact that pseudomonas in the CF lung grow in biofilms is profound," Costerton says. "How about a new class of antibiotics aimed at killing the biofilm phenotype for a change?" Greenberg agrees with this strategy, and he and his colleagues are planning to automate the test that they developed as part of a general scheme for screening thousands of compounds for their ability to disrupt biofilms or selectively attack the bacteria that form them.

A second report from UI researchers, which appears in the 10 October issue of the Proceedings of the National Academy of Sciences, aims at another common complication among CF patients. Ordinarily, antimicrobial compounds are secreted into the fluid layer overlaying the epithelial lining of the lungs, but this process is curtailed in CF patients. Joseph Zabner and his colleagues at UI now say that treating such surfaces with the simple sugar xylitol may enhance this natural defense system and perhaps benefit CF patients.

Several of those naturally secreted antimicrobial compounds, including lysozyme, lactoferrin, secretory leukopeptidase, and phospholipase, are more effective if salt levels remain low in the airway surface fluids, according to Zabner. However, in CF model studies, those levels are "high," he says. "We thought that if we could lower the salt concentration in the liquid, it might be a way to prevent onset of infection in the lungs of people with CF." Reports by other researchers indicate that xylitol behaves as an impermeable osmolyte that, when appropriately applied to local tissue surfaces, can help to control either tooth decay or inner ear infections, he notes.

Those findings prompted Zabner and his collaborators to try xylitol in their CF lung model system. Adding xylitol indeed reduces salt concentrations in fluids overlaying CF-affected and normal lung epithelial layers, without compromising the potency of antimicrobial compounds that are secreted on such surfaces (and also without serving as a nutrient source for the microorganisms that occur along such surfaces). When xylitol reduces salt levels along such surfaces, epithelial cells there apparently can secrete more of the antimicrobial agents that high salt levels tend to block, Zabner explains.

A similar phenomenon seems to be at work in epithelial cells lining the human nasal passage, according to tests conducted on healthy volunteers, Zabner and his colleagues find. After xylitol or saline solutions are sprayed in the nostrils of such volunteers, the adherence and growth of microbial flora is reduced along the nasal surfaces of those subjects who were treated with xylitol, but not in those treated with saline, he says. The basic similarity of the nasal and lung epithelia, fairly constant levels of bacteria in the nose, and their ease of enumeration make the nose a good starting place to demonstrate these effects of xylitol, he points out.

However, several scientists question whether these findings are related to what Zabner is measuring in the lung CF model system. "Nasal cells are not the same as lung cells," says microbiologist Robert Hancock of the University of British Columbia (UBC), Vancouver, suggesting that direct clinical tests in which xylitol is applied to the airways of CF patients are in order. His UCB colleague David Speert, who studies CF, suggests that the human volunteer studies may be measuring another phenomenon altogether. "I suspect they observed a general anti-adhesive effect rather than, or in addition to, the osmolyte effect they postulated," he says. "The effect would be similar to that we have observed with dextran, which interferes with adhesion of P. aeruginosa to airway epithelial cells."

Brian Hoyle
Brian Hoyle is a freelance science writer from Bedford, Nova Scotia, Canada.