Scientists create first regulatory map of tuberculosis

For most people in the Western world, the mention of tuberculosis is likely to conjure up images of the Victorians. In richer countries, tuberculosis is, for the most part, a thing of the past.

But TB has never completely gone away. In fact, it's still thriving in many parts of the world. So much so that drug-resistant strains of the disease are popping up, making TB more difficult to treat. Up until now, scientists have not had a comprehensive understanding of how the TB bacterium is able to adapt to changing conditions in its host.

In a new study appearing this week in Nature, an international team of researchers has published the first glimpse of the wiring of the Mycobacterium tuberculosis genome. The work essentially maps the network of genes that control the TB bacterium--a feat that was 5 years in the making and involved scientists from Stanford University, Seattle Biomedical Research Institute, Boston University and the Broad Institute, Max Planck Institute of Biology in Berlin, Caprion Proteomics Inc. in Montreal, Brigham and Woman's Hospital, and Colorado State University.

"We've had the TB genome sequenced since 1998. It's been useful but it made clear for us how much else we needed to understand," Seattle BioMed professor David Sherman, one of the study's lead researchers, said in an interview with FierceBiotech Research.

What makes TB so deadly is that is can lay dormant for years and emerge in otherwise healthy people. About a third of the world's population is infected with this kind of latent TB, harboring an inactive form of the bacteria in the lungs. What's more, the disease has the ability to pick up mutations, and TB can transmute in people who don't finish their lengthy medication regimens, which often cause unpleasant side effects. The rise of HIV has compounded the problem, as HIV patients tend to be more prone to TB infection since their immune systems are weakened. In 2011 alone, the active form of TB infected 8.7 million and 1.4 million died.

To create a map of how TB genes are regulated, the researchers, led by Sherman and colleagues Gary Schoolnik of Stanford Medical School and James Galagan of Boston University and the Broad Institute, looked to ChIP-Seq technology to analyze and identify the key genes at work. Using ChIP-Seq, the research team identified where 50 of TB's regulatory transcription factors bound to DNA, providing a map of the genetic connections in the TB genome.

The TB genome contains nearly 4,000 genes, and so far, the scientists have linked the transcription factors to about a quarter of those, making the map the most comprehensive to date. But that's not the end of the story, Sherman said. The team plans to fill out the rest of the map by incorporating the sequences of the remaining transcription factors and their relationship to the TB genome.

Sherman and his colleagues' research could be a boon to drug discovery scientists searching for new ways to combat TB and its drug-resistant forms.

"We've begun to use these networks to look for connections that will help us to drug discovery in dramatically different ways," Sherman said. "This (map) gives us a much better view of the vulnerability of whole pathways, so we could potentially target pathways instead of individual genes."

Sherman is not convinced that all of TB's targets have been found. He hopes the map will help researchers develop targeted drugs or immunological interventions that could interfere with TB's skill at surviving in its host, adding an important weapon to the fight to eradicate TB worldwide.

The project was funded in whole by the National Institute of Allergy and Infectious Diseases.

- read the press release
- and here's the Nature study