Despite decades of research on the bacterium that causes tuberculosis (TB), scientists have not had a comprehensive understanding of how the bacterium is wired to adapt to changing conditions in the host. Now, researchers at Stanford University, Seattle BioMed, Boston University and the Broad Institute, Max Planck Institute of Biology in Berlin, Germany, Caprion Proteomics Inc. in Montreal, Canada, Brigham and Woman's Hospital (Harvard University), and Colorado State University have taken the first steps toward a complete representation of the regulatory network for Mycobacterium tuberculosis. This map of the network of genes that control the TB bacterium will yield unique insights into how the bacteria survive in the host, and how they can be tackled with new drug interventions. The landmark results are published this week in the journal Nature.
The burden of tuberculosis
One third of the world's population is latently infected with TB, harboring the bacteria in a dormant form in the lungs. In 2011 alone, 8.7 million people fell ill with the active form of TB, and 1.4 million died.
For hundreds of years, people have associated reduced oxygen tension with the control of TB. Artificially collapsing an infected lung using a pneumothorax device, or inserting golf ball-sized items into the pleural cavity, were common ways to treat the disease before the rise of antibiotics. Despite the prevalence of these treatment methods, the bacteria appeared to survive in the host, even in hypoxic environments.
"We needed a window into how tuberculosis adapts to change, whether that is a lack of oxygen or a new drug," explains David Sherman, Ph.D., a lead researcher from Seattle BioMed. "In order to do that, we needed to understand how TB is wired-how its genes and the molecules that regulate them are related-so we can see how it changes its behavior depending on the environment."
In order to create a map of how TB genes are regulated, researchers led by Gary K. Schoolnik, Ph.D., at the Stanford Medical School, David Sherman, Ph.D., of Seattle BioMed and James E. Galagan, Ph.D., of Boston University and the Broad Institute, turned to technologies that identified the key players in the system. Using ChIP-Seq, a method to analyze how proteins interact with DNA, they identified where 50 of TB's regulatory transcription factors bound to DNA, thereby providing the wiring diagram of genetic connections.