The removal of a regulator gene that allows the tuberculosis bacterium to remain dormant in laboratory studies could point the way to new treatments for many tuberculosis patients. Research at the University of Washington by Dr. David Sherman, assistant professor of pathobiology in the School of Public Health and Community Medicine, and his colleagues shows that by interrupting the function of this gene, the tuberculosis bacterium is unable to mount the appropriate genetic response. It thus may be unable to become dormant.
His paper, published in the June 19, 2001 edition of the Proceedings of the National Academy of Sciences, may point the way for an effective future treatment of tuberculosis.
“With so many people carrying latent tuberculosis disease and no understanding at present of the nature of the organisms that cause latency, this research is among the first to identify controls on that process,” Sherman said. “Anything that is happening to so many people is important to us all.”
Approximately 1.9 billion people — about one-third of the world’s population — carry the tuberculosis bacterium in their bodies, and about 3 million people die of tuberculosis each year. Approximately one million new cases of tuberculosis are diagnosed in the Americas every year. “No one in the world so far can afford to be complacent about this disease,” Sherman said. “As a colleague once said, the greatest risk factor for tuberculosis is breathing.”
Ninety percent of the people carrying the bacteria may test positive for it, but will never develop the active form of the disease. The body’s normal response to TB infection is to encapsulate the bacteria in a soft mass of tissue called a granuloma. Within the low-oxygen environment of the granuloma, the bacteria are thought to enter a dormant state governed by their genome.
Sherman’s laboratory research shows that if a gene vital to the early stages of this adaptation to the hypoxic environment of the granuloma is incapacitated, the complex, finely tuned genetic response of the organism is interrupted. Sherman suspects the disrupted bacteria may not be able to mount a defense against the body’s immune system.
“Our hypothesis was that the tuberculosis bacteria’s genes are activated in waves,” Sherman said. “If we blunt the first wave of response, we may be able to halt the whole adaptation to a latent state. Several technical advances, including the recent sequencing of the tuberculosis genome and the generation of a whole genome microarray provided us with an effective way to disrupt the function of a particular gene within the bacteria.”
The use of the microarray allowed Sherman and his colleagues to study the expression of each gene in the tuberculosis genome simultaneously. They were able to locate what Sherman said is the one gene that may be central to maintaining latent infections in nearly 2 billion people.
“Interrupting that process,” Sherman said, “could provide a powerful new weapon in the fight against this ancient and deadly scourge. Further research to link the regulator with latent tuberculosis in humans is under way.”
This research is being conducted in the laboratory, rather than in human patients.