Canadians find key step in mounting immune responses to infectious bacteria
LONDON, ON (Aug. 29, 2000) -- Scientists at The John P. Robarts Research Institute and The University of Western Ontario (UWO) have discovered an important step in the molecular pathway involved in the activation of white blood cells, called neutrophils, that mount the first line of defense against invasion by infectious organisms. Neutrophils are attracted to sites of infection in response to their activation by chemical attractant molecules called chemokines. Once at the site of infection, neutrophils kill invading bacteria by either ingesting them or releasing packets of destructive enzymes and toxic molecules. These packets or granules are key to stopping bacterial growth.
While neutrophils represent the first line of defense against bacteria and other invading organisms, in medicine, they represent a double-edged sword. On the good side, they are essential in protecting us against bacterial infection. On the bad side, if too many neutrophils get into an inflamed tissue, they contribute to the destruction of healthy tissue. Consequently, understanding how the granule release process is achieved is essential to controlling the appropriate timing and extent of our bodys immune defense response to bacterial infection.
In the September 2000 issue of the international science journal Nature Immunology, Jana Barlic and coauthors identify the initial signals that are required to release granules from neutrophils. The researchers discovered that in response to chemokine-mediated activation of a receptor protein (CXCR1) on the cell surface of neutrophils, a molecule called ?-arrestin is mobilized to form signaling complexes on granules and causes the release of their toxic contents outside the cell. This work will come as a surprise to many immunologists, since ?-arrestins were originally considered to shut down chemokine-mediated cell responses, explains senior author Dr. David Kelvin.
The research builds on pioneering work from Dr. Stephen Fergusons and other laboratories showing that ?-arrestins may also function as cell signaling molecules. This is the first report showing that ?-arrestin signaling has important impact on human physiology and in particular the activation of our immune defense system, says Jana Barlic, a graduate student working with Dr. Kelvin at Robarts.
With the growing ineffectiveness of many antibiotics, it is increasingly important to foster the ability of our own immune systems to fight off bacterial infection. By identifying ?-arrestin as a key determinant of neutrophil activation and granule release we may be able to start and stop neutrophil killing at will by developing strategies to control ?-arrestin activity, says coauthor Alyson Kelvin. Consequently, the potential to control ?-arrestin activity will not only help to activate neutrophils and fight infection but also shut-off neutrophil activation when our bodys own defenses turn against us in autoimmune diseases. Long-term, the researchers think ?-arrestins will be a valuable target of drug manufacturers to help the immune system work more efficiently.
This study represents only the beginning of what ?-arrestin proteins might control in defending our bodies against infection. We are very interested to see whether ?-arrestins control the killing of virus-infected cells, says Dr. Kelvin. T cells normally kill virus-infected cells but no one knows what controls the killing process. Many of the killer molecules are known, but what starts and stops these processes is unknown. ?-Arrestins may play a role, says Dr. Ferguson. The graduate students and postdoctoral fellows in Dr. Kelvins laboratory are now turning their attention to T cells and viruses.
The work on this Nature Immunology paper was a team effort headed by Drs. David Kelvin and Stephen Ferguson. UWO students, Jana Barlic and Alyson Kelvin, spearheaded the effort putting in many long hours. The study also brought together investigators from multiple disciplines at Robarts and UWO, including Dr. Ross Feldman, Joseph Andrews, Steven Bosinger, Mark DeVries, Luoling Xu, and Tomas Dobransky.
The research was funded by the Medical Research Council of Canada (now the Canadian Institutes of Health Research), the Medical Research Council-Juvenile Diabetes Foundation International, the Heart and Stroke Foundation of Canada, and Premiers Research Excellence Award.
For more information, please contact:
Dr. Steve Ferguson,The John P. Robarts Research Institute
Tel: (519) 663-3825
Irene Posliff, Communications Officer, The John P. Robarts Research Institute
Tel: (519) 663-5777 ext. 1-34409
Dr. David Kelvin, The John P. Robarts Research Institute
Tel: (519) 663-2917