By David N. LeffScience Editor

Of all the nasty, sneaky, treacherous, malicious, downright devilishgerms that infect the human race, a short microorganism with a longname rates among the worst.

Pseudomonas aeruginosa is an air-breathing bacterium that lives insoil and water. There it shows its anti-mankind cloven hoof byreleasing nitrogen from nitrate fertilizers in the soil, therebyimpoverishing its arability.

Of course, to give that microbial devil its due, if the soil's contrarian,nitrogen-fixing bacteria had the field all to themselves, they wouldpull elemental N3 out of the earth's atmosphere, and pile it upunderground forever.

Opportunistic P. aeruginosa also attacks people as individuals, butonly those whose power to resist fatal bacterial infection has beencompromised, typically by burn injury, surgical wounds or theweakened resistance of cancer patients on immunosuppressive drugs.

This microscopic public enemy is rod-shaped, and about 1 micronlong, not counting the whip-like tail or flagellum that propels itthrough the water.

Current treatment of P. aeruginosa infection, said bacterial geneticistJoanna Goldberg, "is by administering antibiotics. But," she added,"that nasty bug is resistant to antibiotics, which is why the therapydoesn't work."

She made the point that a particular persuasion of P. aeruginosatargets the 30,000 Americans with cystic fibrosis (CF), who areamong the people least able to defend themselves. "Pseudomonas isnot considered pathogenic," Goldberg told BioWorld Today, "unlessyou've got a compromised host. And CF is just one of thosecompromisers."

Goldberg's laboratory at Harvard Medical School in Bostoninvestigates the genetics of bacterial polysaccharides. Hercollaborator, immunologist Gerald Pier, researches theirimmunochemistry.

Both are co-authors of a paper in today's Science titled: "Role ofMutant CFTR in Hypersusceptibility of Cystic Fibrosis Patients toLung Infections."

Cystic fibrosis results from a mutated CFTR (cystic fibrosistransmembrane conductance regulator) gene. (See BioWorld Today,Jan. 5, 1995, p.1.) "One such mutation in particular, DF508,"Goldberg said, "causes 70 percent of CF cases. Sixty percent of allCF patients have the P. aeruginosa organism in their sputum. It's amajor cause of lung infection, which is a major cause of CF death."

Goldberg and Pier hypothesized that CF patients are hypersusceptibleto P. aeruginosa infection "because their airway epithelial cells fail totake up the bacteria, and subsequently clear it from the lungs."

They are "actively devising strategies to enhance this internalizationof Pseudomonas by the CF cell lines," Goldberg observed. "If ourtheory is true, you may be able to rid the lungs of the bacteria."

The in vitro and in vivo experiments their paper presents, tend tovalidate that hypothesis.

As starting point, they took airway cells from a CF patient andtransformed them with a human papilloma retrovirus vector thatdelivered either normal or mutant CFTR genes. Then, after growingthese cell lines in vitro, they exposed them to P. aeruginosa cultures.

Finally, they doused this brew with high-dose gentamycin antibiotic."The idea being," Goldberg explained, "that after the cells haveincubated with the bacteria for a while, if the bacteria go into thoseeukaryotic cells, they are protected from the action of the antibiotic.Any bacteria on the outside," she continued, "will be killed."

Although P. aeruginosa are resistant to therapeutic doses ofantibiotic, the super-human concentration of gentamycin in the team'sassay was enough to do them in. As they reported, "Cells expressingthe normal, unmutated CFTR ingested significantly more P.aeruginosa than did those expressing the mutant DF508 gene."

Having thus imitated the infectious mechanism at the cellular level,the Harvard co-authors went on to reproduce in vivo the way a smallCF patient encounters his or her first mugging by a P. aeruginosabacterium.

"We used newborn mice to try to mimic what happens when a childfirst inhales the bacterium from the environment, and then becomesinfected," Goldberg said. The result: "Mice to whom we gave thecomponents of the bacteria that inhibited uptake by the epithelialcells in our in vitro experiments had reduced clearance of the bacteriain the in vivo situation."

This phenomenon throws light on the still-untried concept of avaccine. Goldberg explained: "Bacterial LPS normally divide intothree parts: an endotoxin, a core and an `O antigen,' which extendsout from the bacterium's cell." A priori, this O antigen should have abearing on P. aeruginosa vaccines under development, but for thefact, Goldberg said, that "the CF-specific strains actually turn offproduction of those potentially immunogenic O side chains. That,"she pointed out, "has been one of the problems with developing avaccine based on the LPS, which many bacterial vaccines are basedon."

In short, P. aeruginosa bats last again.

But Pier and Goldberg haven't given up. "What we would like to donext," she said, "is to use this information we've just reported toenhance a CF patient's ability to get rid of the infection. So we'll belooking at the cystic fibrosis transgenic mouse model to see if thisphenomenon holds up. Not for gene therapy, but to show if theirproblem lies in clearance of the infection from their lungs."

She concluded: "It may eventually lead to a rational therapeuticapproach, although we're not quite ready to talk about that yet." n

(c) 1997 American Health Consultants. All rights reserved.