Genes crucial in the control of Tuberculosis found by Gladstone researchers

Controlling a tuberculosis infection requires an interplay of a distinct set of
genes and immune system cells. Researchers at the Gladstone Institute of
Cardiovascular Disease 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.

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.

“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 associate professor of
medicine.

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.