StemCell Therapy

ScienceDaily (June 21, 2012) A team of researchers led by UC Davis Health System has found that human alpha-defensin 6 (HD6) -- a key component of the body's innate defense system -- binds to microbial surfaces and forms "nanonets" that surround, entangle and disable microbes, preventing bacteria from attaching to or invading intestinal cells.

The research describes an entirely new mechanism of action for defensins, an important group of molecules known to bolster the defenses of circulating white blood cells, protect cellular borders from invasive pathogens and regulate which "friendly" microbes can colonize body surfaces. The discovery provides important clues to inflammatory bowel diseases, especially Crohn's disease, which may be caused, in part, by deficiencies in HD6 levels or function.

A paper describing the work appears in the June 22 issue of the journal Science.

"During the past 25 years, researchers have learned a lot about the biological function of defensins, but the role of HD6, a particular molecule that is highly expressed in the intestines, was a mystery," said Charles L. Bevins, professor of microbiology and immunology at UC Davis. "We now know that HD6 has a very unique role in the body's innate immune system. Its ability to latch onto microbial surfaces and self-assemble to cast a fibrous net around bacteria, including pathogens like Salmonella and Yersinia, as well as fungi and protozoan parasites, gives the intestine, a critical part of the body, a powerful and broad spectrum of defense against potential threats."

Bevins is co-senior author of the paper along with his UC Davis colleague Professor Andreas Bumler, an expert in bacterial pathogenesis; UCLA Emeritus Professor Robert I. Lehrer, whose laboratory was the first to discover defensins in the early 1980s; and Professor Wuyuan Lu, a synthetic protein chemist from the University of Maryland School of Medicine whose work provided clues to HD6's subtle and unique properties. First author Hiutung Chu, a graduate student in the Bevins lab who is now a fellow at the California Institute of Technology, was a driving force on the nine-year quest to solve the HD6 puzzle.

About the protein HD6

Defensins are a family of structurally related, small peptides with antibiotic activity found throughout nature in plants and animals. Humans make six different alpha-defensins. Two of these, HD5 and HD6, are secreted by Paneth cells, specialized secretory cells located within the folds of the small intestinal lining. HD5 has well-known antibacterial properties while the function of HD6 had been unknown. The defensin-rich secretions of Paneth cells work in conjunction with nearby intestinal stem cells to maintain micro flora balance and renew intestinal cellular surfaces.

Chu's graduate work focused on characterizing the biological activity of HD6 in studies using cultured intestinal epithelial cells and transgenic mouse models. Although Chu and Bevins anticipated HD6 activity would be very similar to other alpha-defensins, which kill pathogens by poking holes in the microbial membrane, their early research studies repeatedly showed that HD6 did not kill bacteria. Puzzled, they then looked for other possible functions, collaborating with UC Davis professors Angela Gelli and Scott Dawson to see if HD6 might kill only certain bacteria, fungi or parasites. It did not.

After two years into the project and feeling frustrated about the negative results, Bevins and Chu carefully reviewed the experimental data. That's when they recognized two crucial pieces of information. The first was that whenever HD6 was added to suspensions of either bacteria or fungi, a white haze, or precipitate, formed in the solution (see image below). The second was that early studies conducted in collaboration with Bumler had shown that while HD6 did not kill the bacterial pathogen Salmonella, it protected transgenic mice from an otherwise lethal infection.

"When we put these two results together, we were able to systematically show that HD6 was inhibiting microbial invasion and uncover HD6's unique structure and function at multiple levels," said Bevins.

Excerpt from:
Immune system molecule weaves cobweb-like nanonets to snag Salmonella, other intestinal microbes

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