New Strategy for Combating Drug-Resistant Tuberculosis

CAMBRIDGE, Mass. — Using a method of surveying an entire mammalian genome, scientists have discovered that an immune system protein may play a previously unsuspected role in quelling the spread of tuberculosis infection. The finding has implications for devising new therapies for tuberculosis (TB), especially for the drug resistant strains that now affect some 50 million people world wide. The study, reported in the June 10 issue of the Proceedings of the National Academy of Sciences, was led by Dr. Richard Young at the Whitehead Institute for Biomedical Research.

"We believe this is the first time that scientists have used a survey of the entire genome to identify genes turned on by infectious agents. We suspect that this method (strategy) will become a powerful new weapon in the war against other microbes, including HIV," says Dr. Young.

The scientists discovered that the immune system protein, called osteopontin, is produced by macrophages, the sentinels of the immune system. Macrophages normally engulf infectious organisms and recruit other immune cells to keep infections at bay. But Whitehead scientists found that TB-infected macrophages turn on the gene for osteopontin, resulting in increased production of the osteopontin protein. The scientists suspect that the high levels of osteopontin attract other immune cells to the site of infection and result in the formation of granulomas, decaying masses of tissues around the TB bacterium, that characterize the pathology seen in TB patients' lungs.

"In essense, by turning on osteopontin production, macrophages seem to help the immune system wall off the bacterium from the rest of the body," says first author Dr. Gerard J. Nau, a physician-scientist from Massachusetts General Hospital in Boston who works in the Young laboratory. "It is our own immune system's response that leads to the granulomas that can be detected on patients' chest X-rays." The scientists also found increased levels of osteopontin in silicosis, another disease in which granulomas occur due to inhalation of silica particles.

Preliminary studies using mice that lack the gene for osteopontin indicate the protein has an important role in how a host handles infections, says Dr. Young. He and his colleagues found that the osteopontin gene is activated against the TB bacterium but not against another more common bacterium, Escherichia coli. "These findings suggest that osteopontin is produced by the immune system to protect against TB and therefore may represent a new direction for therapy." says Dr. Young. Immune system chemicals, called cytokines, have been used successfully as therapies in other diseases such as anemia and neutropenia (low numbers of white blood cells).

Tuberculosis affects millions of people world wide, and it is the leading cause of death in many developing countries, currently killing more adults each year than AIDS, malaria, and all other tropical disease combined. The World Health Organization estimates that at least one third of the world's population is infected with Mycobacterium tuberculosis, the bacterium that causes TB. Experts predict that 300 million more people will be infected in the next decade and 30 million of them will die from TB.

In recent years, the emergence of drug resistant forms of TB and the AIDS epidemic have aggravated the worldwide pandemic. The World Health Organization now believes that the human population is at a risk for a new and deadly epidemic of drug resistant TB.

"Conditions have never been more perfect for a major global epidemic of drug-resistant TB. Worldwide, we have increasing numbers of individuals with AIDS and of individuals with drug resistant TB being treated inappropriately with our best anti-TB drugs. We can waste no more time learning how to better control TB," says Dr. Young. He says that information from the human genome project will become increasingly important in our efforts to combat emerging and re-emerging microbes.

Other TB Facts of Note:

Most people in the world who have AIDS die of tuberculosis.

TB is the single leading cause of infectious disease deaths in women.

TB likely creates more orphans in the world than any other infectious disease.