A new paper reveals a novel threat-sensing mechanism
Immune defenses recognize a variety of signals and patterns to detect pathogens and other threats. In a new paper in the journal Cell, the Doudna lab and collaborators at UC San Diego reveal a novel immune mechanism in the bacterial immune system Hachiman: sensing genome integrity.
Bacteria have evolved numerous ways to defend against bacteriophages, the viruses that infect them, including the famed CRISPR-Cas9 system. The Hachiman system was identified years ago, but until now, its immune mechanism was a mystery. The researchers were particularly interested in Hachiman because, like CRISPR systems, it was known to have a protein that unwinds DNA and/or RNA.
What the researchers uncovered through a combination of in vitro, in vivo, and striking microscopy work, is that Hachiman recognizes DNA damage through breaks to the structure of the DNA double helix. When this signature of an infection is recognized, the Hachiman system clears the host bacterial cell of all DNA: that of the bacterium itself and of the infecting bacteriophage, leaving an inert “phantom cell” behind. The sacrifice stops the infected bacterial cell from spreading viral infection to nearby cells.
“Where you have immune systems, you have patterns that can be recognized against foreign pathogens,” says co-first author Ben Adler, a postdoctoral researcher in the Doudna lab. “If you can figure out the patterns that are being recognized by immune systems, you can figure out new ways to program them and discover new central themes in biology.”
In other words, by learning what immune systems know, we can learn more about the basic biology of different organisms.
“Recently, because there’s been such an explosion in the amount of genomic data, we’ve come to discover that bacteria actually encode many, many additional immune systems,” says co-first author Owen Tuck, a Doudna lab graduate student. “And one of the most amazing parts of this is that some of these are actually similar to immune mechanisms that are in eukaryotes, including humans. There’s the opportunity both to learn about cool stuff happening in microbes and then also to extend that knowledge to learn things about ourselves.”
Immune systems are also a rich source of tools for molecular biology research and medicine. Restriction enzymes, antibodies, and CRISPR-based genomic tools are a few of the most exciting and impactful tools co-opted from natural immune systems. Will Hachiman be next? Only time can tell.
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