Defending against staph

July 1, 2007

New research has found that human beta-defensin 3 (HBD3) secreted by keratinocytes can kill pathogens within 15 minutes of contact. Internalization of the pathogen into the cell is not required for its destruction.

Key Points

Internalization of the pathogen into the cell is not required for its destruction. The findings could lead to the development of new therapeutic approaches to controlling infection.

"What surprised me was how quickly and effectively keratinocytes can respond to kill the bugs, because they are dying within 15 minutes," says Donald Y.M. Leung, M.D., Ph.D. He led the research team that made the discovery at the National Jewish Medical and Research Center in Denver.

Dr. Leung's study used a human skin explant model to look at the interaction of labeled Staphylococcus aureus with keratinocytes. It found that within five minutes, the pathogen had become associated with keratinocytes, and within 15 minutes the keratinocytes had internalized bacterial debris. Additional work showed that normal keratinocytes killed two to three log more bacteria per cell than HaCaT cells, but fewer bacteria than neutrophils.

He also determined that internalization of the bacteria is an active cellular process, not an invasion of the cell by the bacteria. There is a suggestion that preventing internalization might even enhance killing of the pathogen.

Dr. Leung explains that keratinocytes and cells of the adaptive immune system, such as macrophages and neutrophils, both express toll-like receptors and complement receptors that recognize the presence of bacteria.

"We don't know exactly which molecules the bacteria is binding to trigger this secretion of HBD3," he says.

There may be more than one signaling pathway to recognizing the pathogen, he says.

HBD3 probably resides close to the cell surface because "the data suggests that when the bacteria come in contact with the surface of the cells, the molecules are secreted, immediately killing," he says. "And subsequently, the cells take up the debris."

Two functions?

It may well be that internalization has a dual function, to both present fragments on the cell surface for the adaptive immune response to recognize and to inhibit the inflammatory response so that it does not overreact when the innate response has the situation under control.

Other antimicrobial peptides (AMPs) are induced with exposure to S. aureus, but when Dr. Leung and his colleagues measured the killing power of each individually, most had modest effect. Only HBD3 was sufficiently lethal and plentiful to accomplish the task of clearing the bacteria. However, he acknowledges that other AMPs may have a synergistic killing effect with HBD3.

Free-floating S. aureus are relatively impervious to host cell defenses. It may be that the act of binding to keratinocytes alters the surface structure of the pathogen, making it more vulnerable to HBD3, while at the same time bringing it more proximate to greater concentrations of AMPs.

Dr. Leung says there is a lot of cross-talk between the innate and adaptive immune responses, where the innate immune response is shaping the adaptive immune response, depending on what kind of pathogen is invading the body.

"You want an inflammatory response so that you can create a host defense against invaders like bacteria, but if it's too much, then the human subject starts getting symptoms such as a rash," he says. "It may even trigger disease."

He sees the potential for applying this information to developing new therapeutic approaches to controlling infection.

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