| Trapping Tuberculosis |
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6 April 2005, for ScienceNOW In a big step toward understanding how genetics confers immunity to tuberculosis, researchers have identified a gene in mice that helps them restrain the bacterium behind the disease. A study is now underway on the human version of the gene to see if it serves a similar function. Although Mycobacterium tuberculosis infects approximately one-third of the world's population, only about 10% show any symptoms. In those who do, the disease is often dire, destroying large tracts of lung tissue and killing 2 million people annually. Genetics plays a role in TB susceptibility; that's long been clear from comparisons of mouse strains and human twins, for example. Yet specific genes for resistance have been difficult to pin down. Now researchers have found a gene in mice that plays a major role in containing M. tuberculosis. The researchers, led by immunologist Igor Kramnik of the Harvard School of Public Health in Boston, Massachusetts, found that in a strain of mice highly susceptible to the bacterium, a gene called Ipr1 is not active, possibly because of a mutation in the gene's regulatory sequence. The researchers were able to restore TB resistance by adding an intact copy of the gene and its regulatory regions from a resistant mouse.The team's studies of mouse immune cells suggest how Ipr1 makes a difference: Macrophages that express the gene tend to die in a controlled manner called apoptosis, but nonexpressers die by necrosis, a messy cellular meltdown. Apoptosis is thought to help contain the disease by forming solid clumps called granulomas, while necrosis and associated inflammation help the bacteria multiply and spread between hosts. The gene also improved resistance to another pathogen, Listeria monocytogenes, suggesting it plays a general role in immunity. The researchers, who report their findings 7 April in Nature, say a related gene exists in humans. Work is now underway to see if the human gene also confers TB resistance. "The work is outstanding, marking a potential breakthrough" in understanding how hosts cope with pathogens like M. tuberculosis, says immunologist Tom Ottenhoff of Leiden University Medical Center in the Netherlands. He says he's "optimistic" that the findings will shed light on how TB spreads and how it can be treated in humans. |