Until recently no one knew exactly how the tuberculosis bacteria performed its chameleonlike feat or how to stop it. Now Stanford University Medical Center researchers have begun to understand how Mycobacterium tuberculosis orchestrates its impeccably timed game of hide-and-seek.
"This is an extraordinarily successful survival strategy," said Gary Schoolnik, MD, professor of medicine and of microbiology and immunology at Stanford's School of Medicine. "We're trying to understand how the host's immune system induces and maintains this state of latency." Schoolnik will make his presentation Sunday in Denver at the annual meeting of the American Association for the Advancement of Science in a session called "The Future of Functional Genomics II."
Schoolnik and his colleagues capitalized on the availability of the complete genome sequence of Mycobacterium tuberculosis and the versatility of DNA microarrays to compare the gene-expression profiles of replicating bacteria and bacteria that had been coaxed into latency in the lab. They identified 48 genes involved in the physiological and morphological changes that occur when the bacteria enters its extended hibernation.
"We've discovered a genetic program that contributes to the organism's capacity to persist and which explains, in part, the mechanism for reactivation," said Schoolnik. The secret lies in the ability of the bacteria to respond to a combination of low oxygen levels and increased amounts of nitric oxide - a molecule secreted by activated immune cells in the host - by turning on the expression of latency-inducing genes.
These genes transform the physiological state, biochemical pathways and structure of the organism - changes that contribute to long-term persistence. Falling levels of nitric oxide, often a hallmark of an immune system weakened by disease or age, coupled with robust oxygenation in the upper lobes of the lung, are a wake-up call; reactivation of the dormant bacteria leads to clinical symptoms, including coughing.
This delicate balance between latency and virulence seems to represent an uneasy truce between bacteria and host resulting from thousands of years of co-evolution, said Schoolnik.
"Latency is like a contract between the host and the bacteria," he said. "As long as the levels of nitric oxide remain constant, the bacteria will not divide. It's a kind of mutualism."
Although only a minority of latently infected people ever experience reactivation of the tuberculosis bacteria, the likelihood of reactivation approaches 100 percent in people living with chronic HIV infection. "Our model helps explain the 'evil conspiracy' between AIDS and tuberculosis," said Schoolnik, "and re-emphasizes the potential for AIDS to produce an explosive epidemic of tuberculosis in Third-World countries."
Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at http://mednews.stanford.edu.
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