Genes crucial in the control of tuberculosis found by Gladstone researchers

July 02, 2001

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.

"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.

University of California - San Francisco

Related Tuberculosis Articles from Brightsurf:

Scientists find new way to kill tuberculosis
Scientists have discovered a new way of killing the bacteria that cause tuberculosis (TB), using a toxin produced by the germ itself.

Blocking the iron transport could stop tuberculosis
The bacteria that cause tuberculosis need iron to survive. Researchers at the University of Zurich have now solved the first detailed structure of the transport protein responsible for the iron supply.

Tuberculosis: New insights into the pathogen
Researchers at the University of W├╝rzburg and the Spanish Cancer Research Centre have gained new insights into the pathogen that causes tuberculosis.

Unmasking the hidden burden of tuberculosis in Mozambique
The real burden of tuberculosis is probably higher than estimated, according to a study on samples from autopsies performed in a Mozambican hospital.

HIV/tuberculosis co-infection: Tunneling towards better diagnosis
1.2 million people in the world are co-infected by the bacteria which causes tuberculosis and AIDS.

Reducing the burden of tuberculosis treatment
A research team led by MIT has developed a device that can lodge in the stomach and deliver antibiotics to treat tuberculosis, which they hope will make it easier to cure more patients and reduce health care costs.

Tuberculosis: Commandeering a bacterial 'suicide' mechanism
The bacteria responsible for tuberculosis can be killed by a toxin they produce unless it is neutralized by an antidote protein.

A copper bullet for tuberculosis
Tuberculosis is a sneaky disease, and the number one cause of death from infectious disease worldwide.

How damaging immune cells develop during tuberculosis
Insights into how harmful white blood cells form during tuberculosis infection point to novel targets for pharmacological interventions, according to a study published in the open-access journal PLOS Pathogens by Valentina Guerrini and Maria Laura Gennaro of Rutgers New Jersey Medical School, and colleagues.

How many people die from tuberculosis every year?
The estimates for global tuberculosis deaths by the World Health Organisation (WHO) and the Institute for Health Metrics and Evaluation (IHME) differ considerably for a dozen countries, according to a study led by ISGlobal.

Read More: Tuberculosis News and Tuberculosis Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to