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Bottling immunity
New insights into therapies on tuberculosis are coming from the immune cells that already know how to control it
For the two billion people worldwide with latent tuberculosis infections, the clock is ticking. For them, the TB bacteria are functioning as a terrorist sleeper cell would; they are lying low until they can make a coordinated attack.
As Tom Ridge could tell you, it’s a devilish strategy.
But Rockefeller scientists John MacMicking and John McKinney plan to make use this insidious trait in the fight against the disease. By studying how a healthy immune system responds to the TB pathogen and keeps it in check, they’ve identified a pathway that appears to inhibit its growth.
TB’s existence is based largely on stealth. In 90 percent of those infected, it’s not life threatening. People with these latent TB infections don’t feel sick and they can’t spread the disease to others — the body’s immune system is essentially holding the microbe at bay. But when the immune system weakens, as happens with age or disease, the pathogen can surge to life, triggering the full-blown respiratory meltdown that allows TB to claim more human lives each year than any other bacterial pathogen.
The immune system pathway discovered by McKinney and MacMicking, called LRG-47, may explain the body’s ability to hold TB at bay for as long as it does. Studies of cells infected with TB suggest that the LRG-47 pathway cuts off the bacteria’s ability to reproduce inside the immune system cells where they hide. Though the precise mechanistic details haven’t been worked out, there’s now powerful evidence of this: In last week’s issue of the journal Science, MacMicking and McKinney report that when the LRG-47 pathway is removed in genetically engineered mice, the mice become profoundly susceptible to TB infection.
“By learning more about how the immune system successfully operates during infection, we may be able to manipulate the host-pathogen relationship in a way which favors human health,” says MacMicking, a research associate in McKinney’s Laboratory of Infection Biology. “We’re looking for immune pathways which could render the TB bacillus vulnerable.”
The current treatment for TB, a combination of three potent antibiotics administered for six to nine months, is physically and financially draining on patients and downright prohibitive in developing countries with overburdened healthcare systems. And when the full course of drugs isn’t carefully followed, the bacteria build up resistance to the antibiotics.
“This discovery is exciting because it provides a much sought-after link between immune cell activation and TB inhibition. LRG-47 opens up a new way of thinking about the problem. It’s the first step in a biologic process which one day could be mimicked chemically and therapeutically,” says MacMicking.

October 31, 2003



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