Scientists
have known for a century that viruses attack and sometimes kill bacteria, much
the way humans come down with the flu. But only recently have they begun to
understand the biochemistry that happens as bacteria and virus strive for
competitive advantage, with far-reaching implications for medicine and more.
A
decade ago, "nobody thought that bacteria had sophisticated, adaptive
immune systems," said Blake Wiedenheft, associate professor in Montana
State University's Department of Microbiology and Immunology in the College of
Letters and Science and College of Agriculture.
Since
then, however, researchers have
discovered a mechanism by which bacteria wield machine-like molecules that detect and
destroy invading viruses. This immune response is called CRISPR, an acronym
describing how bacteria incorporate fragments of viral DNA into their own
genome as a way to recognize and fight viruses in the future.
For
Wiedenheft, an internationally recognized expert in the field, the growing
knowledge of CRISPR raised other questions: Have viruses found ways to subvert
the bacterial defense? And if so, how?
"Viruses
are formidable," Wiedenheft said. "And we're starting to learn about
the creative repertoire of strategies they have evolved to evade detection but
their hosts."
Using
a powerful electron microscope and cutting-edge image processing techniques,
Wiedenheft and his collaborator, Scripps Research Institute associate professor
Gabriel Lander, could see a complex CRISPR molecule respond to viral DNA by
unfurling a molecular arm that Wiedenheft likens to a "beacon."
Lander and Wiedenheft are lead co-authors of the paper.
The
beacon is like "a red flashing light that signals danger," serving as
a biochemical cue for other CRISPR molecules to destroy the virus, Wiedenheft
explained.
The
surprise came when the researchers realized that the beacon resembled a protein
that the virus was known to produce. The match was improbably precise.
"It
appears that the virus has stolen the beacon and is using it as a decoy,"
Wiedenheft said. In other words, by releasing molecules of the beacon-like
protein into the bacteria, the virus could confuse the CRISPR alert signal.
"It's brilliant and devious."
It's
not the first time that Wiedenheft's team has discovered such viral subversion.
In 2014, his team and a group of international colleagues published a paper
showing that so-called "anti-CRISPRs" could block the bacterial
immune system using a combination of strategies. In 2017, they published results
showing that two other anti-CRISPRs prevent the immune system from recognizing
a virus, either by mimicking DNA or functioning like crude wedges that jam the
viral surveillance machines.
What
makes the most recent discovery significant is that it's the first observed
case of a virus mimicking an actual CRISPR protein, Weidenheft said.
According
to Wiedenheft, it's an open question as to whether the virus "stole"
the beacon -- that is, directly appropriated it -- or whether it evolved
independently.
"Next,
we want to test this evolutionary hypothesis directly," and see if the
virus can be caught in the act, Wiedenheft said.
If
they succeed in that, it would open possibilities for crafting anti-CRISPRs in
the lab, which could have significant implications in medicine, Wiedenheft
said. Viruses are already used as alternative treatment against
antibiotic-resistant bacteria, and engineering their ability to overcome the
natural CRISPR defense could further help to treat harmful bacteria.
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