Aug. 19, 2008
Image: A scanning electron micrograph of the surface of a fruit fly following infection with the bacteria Pseudomonas aeruginosa (the rod-shaped objects in the image).
Fruit flies help UI team understand bacterial infections
Sometimes it may be a good idea to "shoot the messenger": University of Iowa researchers and colleagues have shown that destroying a messenger molecule used by the bacterium Pseudomonas aeruginosa (P. aeruginosa) protects against infection-related death in fruit flies.
The research team, led by Joseph Zabner, M.D., professor of internal medicine in the UI Roy J. and Lucille A. Carver College of Medicine, used fruit flies to learn more about P. aeruginosa, which is a major cause of infections in individuals who are hospitalized, have burn wounds or have cystic fibrosis. The research, which was published Aug. 14 in the online edition of the Journal of Clinical Investigation (http://www.jci.org), suggests that the bacteria's cell-to-cell signaling system is key to the bacteria's ability to cause disease.
Furthermore, the researchers showed that a human protein, which can degrade the messenger molecule, interferes with the communication system and significantly reduces the bacteria's virulence.
"It is interesting that evolution leads to a mechanism that protects against bacterial infections by modulating their virulence without killing the bacteria," Zabner said. "This approach may have important implications in the development of new therapies against bacterial infections that are not antibiotics."
Many bacteria, including P. aeruginosa, use cell-to-cell communication systems called quorum sensing to regulate gene expression in response to environmental changes. Quorum sensing allows the bacteria to survive and thrive in different conditions.
Previous studies had suggested that a quorum-sensing molecule used by P. aeruginosa, called N-3-oxododecanoyl homoserine lactone (3OC12-HSL), is also important for the bacteria's deadliness. In addition, it is known that many organisms, from worms to humans, contain a family of proteins called paraoxonases (PON) that can degrade 3OC12-HSL.
Fruit flies, which have proven to be a useful model for investigating host-pathogen interactions, lack PON proteins. Zabner and his team, including lead study author David Stoltz, M.D., Ph.D., UI assistant professor of internal medicine, capitalized on this feature to test their ideas that disruption of the bacteria's quorum-sensing system would alter its virulence.
They showed that P. aeruginosa'a ability to produce fatal infection depends on the presence of 3OC12-HSL. Bacteria that cannot make 3OC12-HSL are less virulent than normal bacteria, and supplementing the deficient bacteria with synthetic versions of the messenger molecule restores the bacteria's lethality.
The study also shows that flies expressing active human PON1 protein are protected from the bacteria's normally lethal effects, suggesting that PON1 is important for protection against lethal P. aeruginosa infection via its ability to interfere with quorum sensing.
The findings suggest that targeting quorum-sensing molecules or manipulating PON function might provide new approaches to therapy for infections caused by quorum-sensing pathogens.
Although there are currently no genetic diseases caused by malfunction of PONs, these proteins are highly variable in humans. The knowledge gained in these studies should prompt further investigation to find out whether the genetic variability in humans can explain why some people get certain infections and others do not. Moreover, the findings could lead to better understanding of how humans interact with normal bacteria. Finally, if PON genetic variability correlates with a disease not currently considered infectious -- coronary artery disease for example -- it could help identify quorum-sensing bacteria that might be the cause of these diseases.
"For some time now, studies have suggested a possible link between paraoxonase function and cardiovascular disease," Stoltz said. "Interestingly, some researchers have proposed that bacterial infection and inflammation contribute to the pathogenesis of heart disease. Our results from this study might link these two ideas."
In addition to Zabner and Stoltz, the research team included Egon Ozer, M.D., Ph.D., at Feinberg School of Medicine, Northwestern University; Peter Taft, UI research assistant; Marilyn Barry, at Tufts University School of Medicine; Lei Liu, Ph.D., UI postdoctoral fellow in internal medicine; Peter Kiss, Ph.D., UI research assistant; Thomas Moninger, assistant director of the UI Central Microscopy Research Facility; and Matthew Parsek, Ph.D., at University of Washington.
The study was funded in part by grants from the National Institutes of Health and the Parker B. Francis Fellowship program.
STORY SOURCE: University of Iowa Health Science Relations, 5135 Westlawn, Iowa City, Iowa 52242-1178
MEDIA CONTACT: Jennifer Brown, UI Health Care Media Relations, 319-335-9917, email@example.com