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TB organism's secret life exposed in hail of systems-biology measurements

paparazziIf you want to track a criminal, it's not enough to have a high-resolution photo of one nostril. Much better to have a mug shot of the malefactor's entire face - or better yet, a video that shows how that face's  expressions change with shifting situations. Call it a "systems approach."

A number of scientists from several institutions, spearheaded by Stanford infectious-disease sleuth Gary Schoolnik, MD, have done something like that with tuberculosis. Their investigation's results were just published in Nature.

Technically speaking, TB is on the decline globally. But that's not saying much. Roughly one out of every three people on Earth today is infected by the microbe responsible for the disease. Fortunately, fewer than one in 10 of those so infected will develop symptoms in their lifetimes. But that still leaves tuberculosis in second place among the world's current most lethal infectious diseases - close to 1.5 million deaths annually. An estimated billion souls have succumbed to TB in the past 200 years. Meanwhile, drug resistant TB strains are becoming increasingly common.

Yet the organism's modus operandi remains poorly understood. So, rather than conducting a narrow study of how changes in a given gene's or protein's activity level correlates with disease-relevant characteristics of M. tuberculosis (the TB agent's formal name), the Schoolnik-led team took a systems approach. They went about assembling a global profile of the agent's changing features as it adapts to low oxygen levels - in other words, to life inside its preferred host in the human body, an immune cell called a macrophage. The researchers' objective: an accounting of the extensive regulatory network that determines which genes are active and which are quiet under differing environmental conditions (for example, when oxygen is scarce, versus abundant).

Key to the coordinated activation of numerous genes are proteins called transcription factors, which bind selectively to patches of DNA and instigate the production of proteins specified by the genes in these local regions. Out of the TB agent's 180-plus already-known transcription factors, the team was able to map the activities and interactions of 50 that are involved in, among other things, coordinating the switching on of genes helpful in the breakdown of fatty substances in the macrophage's outer membrane as well as the generation of microbial energy-storage molecules, cell wall components, and substances that increase the crafty organism's virulence and help it outwit an infected person's immune system.

So, still a rough sketch. But look out, bug. The cameras are blazing, there's no place to hide.

Updated 07-04-13: My original post stated, falsely, that tuberculosis has felled more people in the past 200 years than any other infectious disease. In fact, smallpox has been a comparable killer. How quickly we (I) forget. Now eradicated, smallpox took hundreds of millions of lives in the 20th century alone. I hope the size of TB's toll will someday be similarly forgettable. (Kudos to RealClearScience's Alex Berezow for catching my error.)

Previously: Stanford TB project bridges U.S.-North Korea divide, Researchers show way to reduce prevalence, spread of TB in former Soviet Union and Coming soon: A faster, cheaper, more accurate tuberculosis test
Photo by drukelly

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