Scientists have discovered the mechanism that hijacks the immune system's response to tuberculosis, revealing an important new drug target for the disease that kills more than 1 million people each year. Herman Sintim, Ph.D., Purdue University's Drug Discovery Professor of Chemistry, collaborated with scientists at Johns Hopkins University to determine how tuberculosis turns off a human cell's signal to mount an immune response to the bacteria. Their findings were published online on December 12, 2016 in the journal Nature Chemical Biology. The article is titled “Inhibition of Innate Immune Cytosolic Surveillance by an M. tuberculosis Phosphodiesterase.” Tuberculosis is a bacterial disease that results in coughing, fever, night sweats, weight loss, and sometimes death. When Mycobacterium tuberculosis enters a human cell, the presence of its DNA and a molecule that it makes called c-di-AMP alert the cell to the bacteria's presence. The human cell responds by creating a messenger molecule, cGAMP, which signals nearby cells to mount an immune response to kill the tuberculosis bacteria. The human cell also produces another molecule, ENPP1, which degrades the cGAMP. That key step turns off the call for an immune response. "Immune response can involve reactive oxygen and nitrogen species, which can kill the bacteria, but at the same time cause collateral damage and also damage or kill the host cells as well," Dr. Sintim said. "There is a very delicate response to bacteria and stopping that response once bacteria have been taken care of." But the tuberculosis bacterium has found a way to turn off the call for help. By producing a protein called cyclic dinucleotide phosphodiesterase (CdnP), the bacterium reduces the concentration of the cell's messenger molecule, cGAMP, a nucleic acid.
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