No organism on Earth is immune to threats, including bacteria. A class of predatory viruses called phages is one of bacteria's worst enemies, invading the bacterium's interior to replicate and ultimately causing it to lyse. And while bacteria have evolved a range of strategies to combat phage invasions, how they detect these invaders in the first place has been a mystery.
Recently, Luciano Marraffini's team at Rockefeller University published a research paper in the journal Nature titled "Bacterial cGAS senses a viral RNA to initiate immunity".
Bacteria defend against phage infections through the CBASS system, but it has been unclear exactly how phages trigger bacteria to initiate a CBASS immune response. This study demonstrates that a structured RNA called cabRNA, produced by phages when infecting bacteria, is the trigger for the CBASS immune response. This study reveals a conserved mechanism for the activation of innate antiviral defense pathways, a finding that could also help combat the threat of antibiotic resistance.
A number of core immune functions are shared across life types, from eukaryotes such as mammals, plants, and fungi to prokaryotes such as bacteria and archaea. These immune responses must have evolved early in life's existence, such as the virus-sensing mechanism, which relies on a specialized enzyme called cyclase, which in animals is known as cGAS (cyclic GMP-AMP synthetase), and cGAS-like cyclase in bacteria, which is a central component of the CBASS immune response, both of which have only been discovered in the past decade.
CBASS cyclase is thought to be a distant ancestor of cGAS, and there are some differences between them. In infected animals, cGAS detects viral DNA in the cytoplasm of the cell because, normally, DNA is only found in the nucleus, and the presence of DNA in the cell indicates that something is wrong.
Bacteria, however, do not have a nucleus structure, so they must take other approaches. If the bacteria's CBASS system reacted to the mere presence of DNA, it would inevitably lead to severe autoimmunity and an attack on itself. cBASS cyclases look a lot like cGAS, so the researchers hypothesized that they must be sensing something, but what exactly has remained a mystery.
To find the answer to this question, the team focused on the CBASS system in Staphylococcus spp. This bacterium is commonly found in the mouths of dogs, cats, and other animals and, in rare cases, can be transmitted to humans.
Luciano Marraffini's lab had accumulated many staphylococcal and staphylococcal phages over the years, which they screened and found produced something during infection that triggered the activation of the staphylococcal CBASS system. Next, they carefully examined the various molecules produced by these staphylococci, or phages, including DNA, RNA, and proteins. The test results showed that only the RNA produced during phage infection triggered the immune response of the bacteria.
Thus, unlike cGAS in animal cells, which senses DNA that appears in the cytoplasm as a mechanism, CBASS senses specific RNA structures. They named this phage-produced hairpin RNA transcribed from the terminal enzyme subunit gene cabRNA (CBASS-activating bacteriophage RNA). CabRNA binds to the surface of the cyclase, triggering the production of the cGAMP messenger molecule, which in turn activates the CBASS immune response.
Similar to the operation of the viral defense system in humans, upon detection of viral DNA, the human cGAS also triggers the production of cGAMP, which induces the immune system to produce type I interferon, and this antiviral signaling pathway in humans is known as cGAS-STING.
This study also brings up some important questions that deserve further exploration—how and why do phages produce cabRNA, and what is its role?