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Almost 75,000 different bacteria have had their genomes sequenced. Of those, Corbett said this new defense system is found in approximately 10 percent. His team cloned the system, now called CBASS, into a laboratory strain of E. coli that is usually sensitive to phage infection. "We were thrilled to find that CBASS provided nearly absolute immunity to phages," Corbett said.
Digging deeper, the team went on to unravel a number of biochemical and structural details about the CBASS defense system, which contains several proteins. They found that the HORMA proteins sense the infection, then stimulate a second protein to synthesize a second messenger molecule. This molecule in turn activates a nuclease enzyme that destroys the bacterium's own genome, killing the cell and also keeping the phage from replicating and infecting other cells.
After falling out of favor a century ago, phages are once again being explored as a therapy for multidrug-resistant bacterial infections. According to Corbett, researchers including those at the UC San Diego Center for Innovative Phage Applications and Therapeutics might be able to use this new mechanistic information on bacterial immune systems to fine-tune phages to evade these systems, making phage therapies more effective.
"On the other hand, if we can find a way to activate this system with a drug, we might be able to get CBASS-containing bacteria to kill themselves," he said. "Doing something like that really requires that we have a clear understanding of the detailed mechanisms at play."
But first, Corbett said, the biggest question is understanding the sheer variety of CBASS systems.
"We've studied just one of more than 6,000 distinct CBASS systems, each of which encodes a different set of infection sensors, signaling proteins and effector proteins like the nuclease in our system. Understanding how these different sets of parts work together, and how bacteria have mixed and matched them as they've evolved, will give us a more complete picture of how it all works, and how we might best intervene." Source:
University of California - San Diego Journal reference:
Ye, Q., et al. (2020) HORMA Domain Proteins and a Trip13-like ATPase Regulate Bacterial cGAS-like Enzymes to Mediate Bacteriophage Immunity. Molecular Cell . doi.org/10.1016/j.molcel.2019.12.009 .
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