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Posted 10-12-99
CLEVELAND -- Science has long recognized that our body's first line of defense against germs comes from the skin and the membranes that line body cavities. Recent discoveries, however, show that these tissues do more than serve as a physical barrier against intruders.
Researchers such as Case Western Reserve University's Aaron Weinberg are finding that they also produce natural antibiotics that can destroy or inhibit the growth of harmful microorganisms that might otherwise cause infection or disease.
Weinberg, an associate professor in the Department of Periodontics in the School of Dentistry, has received a grant of more than $1 million from the National Institutes of Health (NIH) for a four-year study of this little-understood component of innate immunity.
A microbiologist and dentist, Weinberg has found that certain harmless bacteria, which he calls "the good guys," stimulate the release of these natural antibiotics in human gingiva, or gum tissue. The "bad guys" that can cause diseases, such as periodontitis, do not trigger these antibiotics and may even prevent the good guys from doing so, he explains.
Weinberg has discovered three such natural antibiotics that are produced in normal human gingival tissue upon stimulation by one common bacterium, Fusobacterium nucleatum (F. nucleatum).
His new study, funded by the NIH's National Institute of Dental and Craniofacial Research, has three aims:
Weinberg hypothesizes that non-release, low-level release, or GAP malfunction may predispose an individual to microbially induced infections of the mucous membrane, including periodontitis and ulcerations. Learning how GAPs operate could lead to new avenues for prevention and treatment of such infections.
Beyond that, he believes -- and the NIH agrees -- it can lay the groundwork for important clinical applications, such as using these natural antibiotics to replace conventional antibiotics.
In view of the growing problem of antibiotic-resistant bacteria, Weinberg noted, alternative sources for antimicrobial agents that are effective against disease-inducing bacteria, yet non-toxic to humans, must be found.
"If we can identify the component of the bacterial cell wall that stimulates the release of these natural antibiotics, we can synthesize it," Weinberg said. "Down the road, we could use this to induce the release of the natural antibiotics and prevent infection. We could use it on all sorts of medical devices that go into our bodies, from urethral catheters to dentures, which are common sources of infections."
Weinberg, who joined CWRU in September 1998, said that his research was inspired by a 1995 paper in the journal Science, which reported the discovery of antimicrobial peptides in cows' tongue. "The research was based on a simple question," Weinberg explains. "Since mammalian tongue is constantly colonized by oral bacteria, fungi, and viruses, why don't abrasions to the surface lead to common invasive infections? If we bite our tongue, why don't we get sick?"
The study found that these lingual (tongue) antimicrobial peptides (LAPs) formed a shield around naturally occurring lesions on cow's tongue, thus protecting the animal from infection at the site. When the researchers isolated and cultured the LAP, they found it killed bacteria.
"So if it's in the cow," Weinberg said, "we figured it was in humans."
He and colleagues at the University of Washington (UW) did indeed find comparable antimicrobial peptides in the mouth -- two beta-defensins (hBD-1 and hBD-2) and a cathelin class peptide (FALL39).
This discovery led to the NIH funding for the new study. Weinberg is principal investigator, while one of his UW colleagues, Beverly Dale, a professor of oral biology and dermatology, is co-investigator.
Until recently, immunology research has focused on adaptive immunity, the acquired resistance that is introduced through immunization. Only in the last decade or so have researchers such as Weinberg and Dale begun to explore the mechanics of innate immunity, the resistance to disease that is inborn in humans, other mammals, insects, amphibians, and even plants.
Antimicrobial peptides were first discovered in fruit flies, then frogs, which spurred scientific interest-in the early 1990s-in looking for peptides in mammals, such as pigs and cows, Weinberg said. Since then, two human beta-defensins have been identified in various areas of the body, including the skin of psoriasis patients, airway tissues, the female reproductive tract, and, thanks to Weinberg's research team, in the gums.
This new direction in research was the subject of this year's Benzon Symposium, an international conference in Copenhagen featuring front-line research in medical, pharmaceutical, and related sciences. Weinberg was among a handful of scientists invited to present their research at the August symposium entitled "Molecular Mechanisms of Innate Immunity."
Weinberg thinks the mouth is the perfect arena in which to study antimicrobial peptides. It is easy to access and harbors a myriad of fungi, viruses, and some 300 species of bacteria -- more than any other part of the body. "We're constantly challenged in our mouths, every minute of every day of our lives," he said. "Yet our understanding of what benefit bacteria have in us is rudimentary, other than certain E. coli that inhabit our gastrointestinal tract. But no one really understands the importance of oral bacteria. That's what we're trying to do here at the School of Dentistry."
In addition to the new study, Weinberg said he is exploring other collaborative research possibilities with CWRU's Evan Eichler, assistant professor of genetics; Mitchell Drumm, assistant professor of pediatrics; and Mahmoud Ghannoum, associate professor of dermatology.
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