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The Best Offense Is a Good Defensin
  
By Nancy Touchette

Humans get AIDS, but monkeys don’t. Most humans survive Salmonella infection, but the bacterium usually kills mice. And many animals that lack immune systems, such as insects, octopi, and starfish, resist invading pathogens altogether.

Why some organisms ward off certain infections while others do not may be due, in part, to small proteins called anti-microbial peptides. A new study shows for the first time that a peptide called defensin-5 kills Salmonella typhimurium bacteria, when produced in mice. Charles Bevins of the Cleveland Clinic Foundation in Ohio led the study.


S. typhimurium

“This is a very important study,” says Andre Ouellette of the University of California at Irvine, who has studied defensins for fifteen years. “Previous evidence that defensin-5 is involved in host defense has been circumstantial. This is the first demonstration that the peptide has an effect in vivo.”

The researchers inserted the human defensin-5 gene into mice, which do not normally have the gene. When exposed to high doses of Salmonella typhimurium, these mice did not get sick, while normal mice became profoundly ill and died.

“This is a profound effect,” says Ouellette. “The data are astonishing.”

Bevins became interested in defensins while operating on frogs in the mid-1980s, when he was a postdoctoral student with Michael Zasloff, then at the US National Institutes of Health in Bethesda, Maryland.

“Right after surgery, the frogs would be tossed into pond water,” says Bevins. “Everyone expected that the frogs would die from infection, but infections were rare. At first, we just thought that the frogs were hardy animals, but that didn't sit well with Zasloff.”

Then a study by Hans G. Boman of the Karolinska Institute in Stockholm, Sweden, described a class of peptides with antibacterial properties in moths that prompted the researchers to look for similar compounds in frogs.

“Zasloff found the same type of proteins in frog skin,” says Bevins. “We then looked at the wet mucosal surfaces of the animal and found that they were abundant in the respiratory tract as well.”

Similar proteins were found in rabbits, mice, humans, and monkeys by Ouellette and others, including Robert Lehrer, Michael Selstead, and Tomas Ganz of the University of California Los Angeles. The human genome contains at least 30 genes that code for different types of anti-microbial peptides, including the class known as defensins. Two types of defensins—alpha and beta—are found in humans. Mice carry their own defensin genes, called cryptidins, but they are not particularly effective against Salmonella typhimurium.

So far six alpha-defensins have been found in humans. The alpha defensins feature 31 amino acids. All defensins contain three bridges containing sulfur atoms that stabilize the tightly folded structure.

Three alpha-defensins have been found in human immune cells that can protect them from infection with HIV.

Defensin-5 and -6 are expressed exclusively in the Paneth cells, special cells of the intestine, and appear to target bacteria, including Salmonella.

Researchers do not know exactly how defensins kill bacteria, but several models have been proposed. Bevins favors the notion that the positively charged amino acids of the defensins bind tightly to the negatively charged surface of the bacteria, which allows defensin's lipid-like residues to slither into the bacterial membrane and disrupt it, killing the cell.

The researchers do not yet know whether defensins naturally protect organisms by directly killing unwanted pathogens, or whether they more subtly regulate the flora that prosper in the intestine, which in turn kill off any invading microbes.

Although the new studies offer the promise of a new class of antibiotics, Bevins says this idea may be met with formidable challenges. The major difficulty, he says, is getting the peptides to fold properly with the correct disulfide bridges. Gene transfer is another possibility, but Bevins says this idea may be more “pie in the sky for the moment,” than reality.

“The significance of this may be more in the realm of gaining a better understanding of how pathogens interact with the organism’s own cells and the natural flora in the digestive tract,” he says.

For example, defensins might play a role in inflammatory bowel disease: “At low concentrations, we think of them as antibiotics, because they kill microbes. But at higher concentrations they could and harm the cells of the organism. Then we call them toxins.”

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Salzman, N.H. et al. Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature published online March 19, 2003.
 

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