ScienceDaily (Sep. 6, 2009) — Scientists have deciphered a key molecular circuit that enables the body to distinguish viruses from bacteria and other microbes, providing a deep view of how immune cells in mammals fend off different pathogens.
The new research, which appears in the September 3 advance online edition of the journal Science, signifies one of the first large-scale reconstructions of a mammalian circuit and offers a practical approach for unraveling the circuits that underpin other important biological systems.
Dendritic cells (in green) and other immune cells (in blue) congregate around a blood vessel (in red). (Credit: Image courtesy of Dr. Shakhar Guy
"Our findings address a fundamental question in human biology: how do immune cells recognize various pathogens and use that information to mount distinct responses," said senior author Nir Hacohen, of the Massachusetts General Hospital (MGH) Center for Immunology and Inflammatory Diseases, an assistant professor at Harvard Medical School and a senior associate member at the Broad Institute. "We now have a detailed view of the circuitry that controls this critical process, providing a deeper understanding of immune biology that could inspire novel ways to treat disease and design better vaccines."
"One of the remarkable things about this study is the approach," said senior author Aviv Regev, a core member of the Broad Institute, an assistant professor at MIT and an early career scientist at the Howard Hughes Medical Institute. "Our methods are not only general and applicable to almost any biological system, they are also practical for most laboratory settings. This is an important step that has broad implications for the scientific community."
Cells receive and process information much like computers. Information flows in, is read and processed through a complex set of circuits, and an appropriate response is delivered. But instead of tiny transistors, the internal circuitry of mammalian cells is made up of vast networks of genes and their corresponding proteins. A frontier of modern genomic research is to identify these molecular parts and their interconnections, which reflect the normal — and sometimes faulty — "wiring" that underlies human biology and disease. Until recently, research in this area focused on yeast and bacteria because it was nearly impossible to undertake in mammals.
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Another remarkable finding is the way these regulators operate. The researchers identified a surprising number of connections between regulators and other circuit components, more than 2,300 connections in total. In addition, some regulators seem to control a relatively broad swath of the circuit, including 25 genes or more, while others influence just a handful of genes. "A good analogy is the tuning dials on an old radio," said Amit. "The big knobs provide coarse adjustments, while the little ones tend to be fine tuners."
One intriguing "coarse tuner" is a protein called Timeless. In fruit flies, it controls circadian rhythms, the internal clock that keeps biological processes operating on a 24-hour cycle. In mammalian dendritic cells, however, Amit and his colleagues discovered that Timeless is a chief regulator of anti-viral responses, controlling over 200 genes required to fight viruses.
Another interesting regulator is CBX4, a "fine tuner" that controls the levels of a key protein involved in viral infections. This protein, called IFNB1 (for Interferon beta 1) requires precise control: if a virus is present, it must be highly active, yet if bacteria are the offending agents, its activity should be minimized.
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Journal reference:
Ido Amit, Manuel Garber, Nicolas Chevrier, Ana Paula Leite, Yoni Donner, Thomas Eisenhaure, Mitchell Guttman, Jennifer K. Grenier, Weibo Li, Or Zuk, Lisa A. Schubert, Brian Birditt, Tal Shay, Alon Goren, Xiaolan Zhang, Zachary Smith, Raquel Deering, Rebecca C. McDonald, Moran Cabili, Bradley E. Bernstein, John L. Rinn, Alex Meissner, David E. Root, Nir Hacohen, and Aviv Regev. Unbiased reconstruction of a mammalian transcriptional network mediating the differential response to pathogens. Science, 2009; DOI: 10.1126/science.1179050
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