Controlling a tuberculosis infection requires precise interactions between a
number of different immune cells. Researchers are showing for the first time
that the absence of the gene for CCR2, a receptor on white blood cells known to
be important for cell migration, can have fatal consequences in this setting.
The study is a joint collaboration between the Gladstone Institute of
Cardiovascular Disease and the UCSF Division of Infectious Diseases.
When proteins known as chemokines bind to white cells they initiate a cascade
of events that results in the accumulation of specific groups of cells at the
site of infection or inflammation. This failed to happen in the lungs of CCR2
deficient mice after infection with Mycobacterium tuberculosis, and they
quickly succumbed. 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 in the laboratory of
Israel F. Charo, MD-PhD, at Gladstone. Dr. Charo is a senior investigator at
Gladstone and UCSF professor of medicine.
Published in the July 3rd issue of the Proceedings of the National Academy of
Sciences USA, the discovery also provides a possible explanation for why some
people are more susceptible to tuberculosis than others, said co-author Joel D.
Ernst, MD, UCSF professor of medicine in the 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 speculated. 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, and CCR2 is necessary for this to happen,” Ernst said.
The study also sends a message to pharmaceutical companies who are trying to
find a drug that blocks CCR2. Two years ago Gladstone scientists found that
mice that lacked CCR2 were protected from developing atherosclerotic plaques.
The current finding sounds the alert “that drugs that block CCR2, may
predispose patients to tuberculosis,” said Charo, whose laboratory initially
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
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.