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Bacteria Provide a Frontline Defense

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4:37pm, February 3, 2004
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With some genetic manipulation, scientists have turned mild-mannered bacteria into stout defenders against disease.

Researchers have learned in the past 2 decades how to entice bacteria naturally found in the body to make compounds that fight a variety of ailments. The technique has been limited, however, because these compounds usually stay anchored to a bacterium's surface. Two studies from Europe now demonstrate that the bacteria can secrete such agents–freeing them to more effectively fight disease.

So far, the approach works in mice and rats. If it succeeds in people, the technique could enlist bacteria as frontline troops against infection. The technology could also prove less expensive than another potential strategy—mass production of antibodies in a laboratory—which is being explored in current anti-infection research, says Vincent A. Fischetti, a microbiologist at Rockefeller University in New York City.

Researchers in Italy report success in quickly ridding female rats of Candida albicans, a fungus that causes vaginal yeast infections. C. albicans also causes thrush, a sore throat prevalent in people with compromised immune systems.

The scientists genetically engineered Streptococcus gordonii, a bacterium routinely found in people's mouths, either to display on its surface an antibody that's lethal to the yeast or to secrete that antibody. In a test of 25 female rats with the yeast infection, the rats that received three infusions of the secreting bacteria into their vaginas took less than a week to heal, as did others treated with the common antifungal drug fluconozole. Rats receiving the bacteria that simply display the antibody on their surfaces took 9 days to get well.

Other rats treated with a version of the bacterium with inconsequential genetic changes took 21 days to heal, as did untreated rats, the researchers report in the October Nature Biotechnology. The rats were considered healed when their vaginal concentration of C. albicans had dropped to one-fifth the original amount.

The antibody produced by the engineered bacteria locks onto molecular receptors on C. albicans' cell wall and kills the fungus, says study coauthor Luciano Polonelli, a microbiologist at the University of Parma in Italy.

Fischetti's team, which developed the technique of getting S. gordonii to display new proteins on its surface, has made a strep throat vaccine that they plan to test soon in people.

The Italian study is the first to show an antimicrobial agent effectively secreted from bacteria in a living host, says Fischetti. By releasing these antibodies, the bacteria make them more mobile than anchored proteins so they can reach and dispatch the yeast more readily, he says.

The mucus-lined surfaces of the mouth, throat, or vagina offer obvious proving grounds for the new technology, says Fischetti. About 90 percent of infectious diseases breach the body via the mucus membranes, he notes. Reducing the number of infectious agents at these sites would boost the immune system's ability to fight off disease, he says.

Because S. gordonii's natural environment is the mouth, not the vagina, the rat findings suggest that genetically tweaked bacteria could serve as "workhorses" delivering novel antibacterial factors to specific body locations that are not necessarily their home, says Dennis F. Mangan of the National Institute of Dental and Craniofacial Research in Bethesda, Md.

It's not yet clear how long the tiny bacteria can pump out agents toxic to other microbes. Bacteria modified and reintroduced into their home environment might have longer staying power than bacteria placed in an agreeable but unfamiliar site in the body, Fischetti says.

In other work pitting bacteria against disease, Lothar Steidler and his colleagues at Ghent University in Belgium genetically engineered Lacococcus lactis bacteria to make and secrete interleukin-10, an anti-inflammatory agent. The researchers fed the modified bacteria to mice with inflammatory bowel disease, which causes diarrhea and pain. Within a month, the treatment reduced symptoms in the mice roughly by half, whereas untreated mice with the disease improved only slightly, the researchers reported in the Aug. 25 Science.

The two studies represent "just the beginning of an exciting and potentially generally applicable strategy" for delivering protectants to mucosal surfaces, say Kevin J. Whaley and Larry Zeitlin of Epicyte Pharmaceuticals in San Diego, also in the October Nature Biotechnology.

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