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Release: May 30, 2002

UI study identifies a defense mechanism against biofilm infections

Resistance to antibiotics in chronic bacterial infections is a difficult and sometimes deadly medical problem. During the development of a chronic infection, bacteria often undergo what could be called a lifestyle change; instead of living as individual organisms, the bacteria form community structures known as biofilms that are like cities of bacteria. Bacteria in biofilms are extremely resistant to antibiotics. Findings from University of Iowa investigators shed light on how the body normally prevents biofilm development.

Bacterial biofilms are dense, organized cellular communities encased in a self-produced slime. Living in groups gives the bacteria properties that they do not have as individuals. In addition to being highly resistant to antibiotics, biofilms are also impervious to the body's natural immune defense system. Examples of biofilm infections include lung infections in patients with cystic fibrosis, wound infections in patients with diabetes and burns, heart valve infections (known as endocarditis), as well as most medical device infections.

"Biofilm infections are a major medical problem, and our group is looking for new strategies to treat or prevent them," said Pradeep Singh, M.D., UI assistant professor of internal medicine. "Though the human body is constantly exposed to disease-causing bacteria, biofilms do not normally form unless a person's defenses have been compromised by disease. This lack of biofilm formation suggested to us that the body might have a natural anti-biofilm defense mechanism."

In a new study of biofilm formation by the bacterium Pseudomonas aeruginosa, Singh and his colleagues demonstrate that a component of the body's innate immune system has this previously unknown defense function. These findings offer insight into how biofilms form and might suggest new strategies for preventing biofilms. The study appears in the May 30 issue of the journal Nature.

In an effort to track down potential anti-biofilm substances, the UI team focused on lactoferrin, a component of the body's antibacterial defense system. The researchers found that bacteria grown in the presence of small amounts of lactoferrin were unable to develop into biofilms. As a consequence, these bacteria remained vulnerable to antibiotics and other antimicrobial substances.

"Lactoferrin is present in lung secretions, tears, saliva, breast milk, and other body fluids that come in contact with bacteria," Singh said. "Everywhere this defense is needed, lactoferrin is present in large quantities."

Using time-lapse microscopy to monitor the motion of bacteria, the UI researchers discovered that lactoferrin causes P. aeruginosa bacteria to roam incessantly across a surface instead of forming cell groups or colonies, the first step in biofilm development. Lactoferrin traps iron, making it unavailable to the bacteria. Iron is a critical nutrient for bacteria and is difficult to acquire from the environment. The UI team discovered that low iron concentrations stimulate a specialized form of bacterial surface motion that causes the bacteria to continually move around as individuals, rather than aggregating in groups.

"From the perspective of the host, this may be a fail-safe defense mechanism. If our laboratory studies reflect what happens on human surfaces, this defense may keep bacteria that survive initial killing from forming biofilms," Singh said.

However, Singh explained that the roaming behavior might also benefit the bacteria.

"Humans choose to build cities near food and other resources; these bacteria seem to have evolved a similar, although more primitive, behavior. When they sense iron levels are low, the bacteria keep moving rather than establishing complex communities in an area where a critical nutrient is in short supply," he said.

Singh speculated that understanding how bacteria sense iron levels might allow scientists to manipulate that mechanism and trick bacteria into thinking that the environment has insufficient iron to support the development of a biofilm. This strategy might help prevent the formation of potentially devastating biofilm infections in humans.

In addition to Singh, the UI team included E. Peter Greenberg, Ph.D., the Virgil L. and Evalyn Shepperd Professor of Molecular Pathogenesis and UI professor of microbiology, and Michael Welsh, M.D., the Roy J. Carver Chair in Internal Medicine and Physiology and Biophysics, and a Howard Hughes Medical Institute Investigator. Matthew Parsek, Ph.D., the Louis Berger Junior Professor of Civil Engineering at Northwestern University, was also part of the research team.

The research was supported by the Howard Hughes Medical Institute, the National Heart, Lung and Blood Institute, the National Institute of General Medical Science, the Cystic Fibrosis Foundation and the W.M. Keck Foundation.

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