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Genes Crucial In The Control Of Tuberculosis Found By Gladstone Researchers

Date:
July 6, 2001
Source:
University Of California - San Francisco
Summary:
Controlling a tuberculosis infection requires an interplay of a distinct set of genes and immune system cells. Researchers are showing for the first time that the absence of one of those genes, called CCR2, can have fatal consequences. Without CCR2, which encodes a receptor known to be important in the body's response to inflammation, containing a tuberculosis infection becomes impossible.

Controlling a tuberculosis infection requires an interplay of a distinct set of genes and immune system cells. Researchers are showing for the first time that the absence of one of those genes, called CCR2, can have fatal consequences. Without CCR2, which encodes a receptor known to be important in the body's response to inflammation, containing a tuberculosis infection becomes impossible. The study is a joint collaboration between the Gladstone Institute of Cardiovascular Disease and the UCSF Division of Infectious Diseases. When specific proteins bind to the receptor, a cascade of events ends in signaling a select group of immune system cells to gather at the site of TB infection. In mice that lacked the receptor, those cells did not come together. These mice quickly succumbed to the disease and died. At autopsy, the mice had 100 times more bacteria in their lungs than the normal mice that had the receptor.

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"It was unexpected that CCR2 would be so important in resistance to TB," said lead author Wendy Peters, PhD, a postdoctoral fellow at Gladstone, and at the University of California, San Francisco's Cardiovascular Research Institute. Gladstone is affiliated with UCSF.

Published in the July 3rd issue of the Proceedings of the National Academy of Sciences USA, the discovery also brings to light a possible reason for how Mycobacterium tuberculosis, the bacterium that causes tuberculosis, behaves in the body, said senior author Joel D. Ernst, MD, UCSF professor of medicine, division of infectious diseases.

In 90 percent of people infected, the immune system permanently controls the bacterium. But not in the remaining 10 percent, who go on to suffer the ravages of the disease. Some of these people could have a variant of the CCR2 gene that's not as effective, Ernst said. Roughly one-third of the world's population is infected with tuberculosis.

"What this study shows is that a failure of recruiting the crucial cells can lead to disease. The study identifies a specific gene that can contribute to that," Ernst said.

The study sends a message to pharmaceutical companies who are now trying to find an inhibitor to CCR2 because of a discovery made by Gladstone researchers two years ago: Mice that lacked CCR2 were protected from developing atherosclerotic plaques, said co-author Israel F. Charo, MD, PhD, senior investigator at Gladstone and UCSF professor of medicine, whose laboratory initially discovered CCR2. The current finding sounds the alert that drugs that block CCR2, for the treatment of heart disease, as caused by plaques, or rheumatoid arthritis, may predispose patients to tuberculosis.

"It's raising a potential problem with CCR2 drugs," Charo said.

Ernst said, "If CCR2 antagonists are used to treat or prevent diseases, physicians will need to be aware that the drugs could cause activation of tuberculosis."

Other co-authors of this study include Holly M. Scott, graduate student, and JoAnne L. Flynn, PhD, associate professor, both of the University of Pittsburgh School of Medicine department of molecular genetics and biochemistry; and Henry F. Chambers, MD, UCSF professor of medicine at San Francisco General Hospital Medical Center.

This study was funded by grants from the National Institutes of Health and the Sandler Family Foundation.

The Gladstone Institute of Cardiovascular Disease is one of three research institutes that comprise The J. David Gladstone Institutes, a private biomedical research institution affiliated with UCSF. The institution is named for a prominent real estate developer who died in 1971. His will created a testamentary trust that reflects his long-standing personal interest in medical education and research.


Story Source:

The above story is based on materials provided by University Of California - San Francisco. Note: Materials may be edited for content and length.


Cite This Page:

University Of California - San Francisco. "Genes Crucial In The Control Of Tuberculosis Found By Gladstone Researchers." ScienceDaily. ScienceDaily, 6 July 2001. <www.sciencedaily.com/releases/2001/07/010704093108.htm>.
University Of California - San Francisco. (2001, July 6). Genes Crucial In The Control Of Tuberculosis Found By Gladstone Researchers. ScienceDaily. Retrieved October 31, 2014 from www.sciencedaily.com/releases/2001/07/010704093108.htm
University Of California - San Francisco. "Genes Crucial In The Control Of Tuberculosis Found By Gladstone Researchers." ScienceDaily. www.sciencedaily.com/releases/2001/07/010704093108.htm (accessed October 31, 2014).

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