Scientists discover tuberculosis strategy for hiding in body

Scientists have identified a key trick that tuberculosis bacteria use to lie low in the body for years before going on the attack - a discovery that could open a whole new approach to fighting a disease that kills more than 2 million people around the world each year.

''In terms of public health, there is a long way to go. This is an important step in the right direction,'' said Dr. William Bishai, professor of international health and medicine at Johns Hopkins University.

Researchers from Rockefeller University, Washington University School of Medicine, Albert Einstein College of Medicine and Texas A&M; University reported their findings in Thursday's issue of the journal Nature.

Tuberculosis infects a third of the world's population, according to the World Health Organization, and is getting more deadly as drug-resistant varieties evolve. Though drugs exist to cure TB, they must be given in a complicated regimen over six months to a year, and many people drop out too soon. That enables drug-resistant strains to develop.

A hallmark of TB is that after people inhale the bacteria and their lungs become infected, the immune system walls it off but cannot kill it. The germs can live in a person for years without developing into the disease.

Scientists know that the microbes hide out in white blood cells called macrophages, which normally seek out and destroy invading bacteria. When something weakens the immune system - such as AIDS - the bacteria go wild, bringing on the full-blown disease.

The new work showed that when TB bacteria go into hiding, a phase known as persistence, the immune system triggers a change in the bacteria that lets the germs shift from feeding on carbohydrates to fatty acids.

''It's that switch in metabolism that is required for the bacterium to maintain the infection,'' said David G. Russell, a researcher at Cornell University who was at Washington University when he participated in the work.

Looking more closely at this switch in metabolism, the U.S. researchers found that an enzyme called isocitrate lyase, or ICL, is key to the process.

The researchers developed a strain of TB bacteria that lacked the gene to make ICL. When they infected mice with the bacteria, the immune system was able to kill bacteria in the persistence phase.

Already, the drug company Glaxo Wellcome Inc. is trying to develop compounds that lock onto the enzyme and stop it from working, making hidden TB bacteria vulnerable.

''A drug that targeted persistence would be quite different from conventional TB drugs, which target processes required for bacterial growth,'' said John D. McKinney of Rockefeller University, who initiated the research. He said blocking ICL would have no harmful side effects.

Such a drug could be used in conjunction with other TB medicines.

''The hope is if we can add a drug against ICL to the existing drug regimens, the two of them together will work better than either of them alone and give us a faster cure,'' McKinney said. ''If we can cut it down to a month or less, this will really have an enormous impact.''


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