A molecule that's part of the body's response to injury or infection increases the chance of survival with at least one disease and seems to ensure death with another, according to an international study that included University of Utah researchers.
In the study, mice with a functioning alpha D gene all died of a severe form of malaria, but when it was knocked out, researchers found 1 in 4 lived. Conversely, with a severe form of the bacterium salmonella, mice with alpha D were more likely to live.
While the study confirms the role of alpha D as part of the body's immune response to infection, it shows that it can lead to uncontrolled inflammation that increases malaria's and perhaps other diseases' deadly potential. The research is published in the Dec. 21 issue of the Journal of Immunology online.
"We were trying to determine the function of the (alpha D) molecule," said Dr. Guy A. Zimmerman, professor of internal medicine and director of the U.'s Program in Human Molecular Biology and Genetics, corresponding author for the study. "We thought that alpha D would protect them and if we knocked it out, it would make mice more likely to suffer negative consequences. We found the opposite." In mice, who have many similarities to humans, 100 percent were killed by the malaria if they had a working alpha D gene.
"What that says, among other things, is that under some conditions, the inflammatory system, which is defensive and reparative and which we all need, can turn against the host," he said.
The opposite was true, though, with a highly infective, often fatal form of the bacterium salmonella. Alpha D seemed to confer some kind of protective function. Without it, the mice died faster and in greater numbers.
"This is very clearly an example of the two-edged sword nature of inflammation. In mice, we know based on many, many studies by many people that if the inflammatory system doesn't work right, many infections are more severe," more likely to be caught and more often fatal. "It's critical for protection against infection and for repair. But under some circumstances, with triggers we don't understand, it can turn against the host and contribute to injury and death."
Researchers now need to dissect the events in mice with and without alpha D to find the molecular and cellular explanation of how it works and how it goes awry, Zimmerman said.
Alpha D is part of a family of receptor proteins called integrins, found on cell surfaces. It helps the cells receive and process information and stick to other cells. Among other things, it helps white blood cells called macrophages detect pathogens and systemic infections in blood. That's why researchers thought it would prove protective with severe malaria.
The findings don't lead to a new therapy, but it's more information that can be used against severe malaria, which kills 2 million people worldwide each year, most of them children. A 25 percent survival rate in humans would mean a half-million lives saved annually.
Zimmerman said the researchers found some preliminary evidence that alpha D may increase inflammation in the brain and probably the lungs, which may explain the higher death rate.
As for the mice with salmonella, a bacterial blood infection, when alpha D was knocked out, the mice all died, but in cases where alpha D was functioning, 15 percent lived.Study collaborators included researchers from the U. program; the Instituto Oswaldo Cruz, Rio de Janeiro, Brazil; Tokyo Medical and Dental University; Lerner Institute, Cleveland; and Oklahoma Medical Research Foundation, Oklahoma City.
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