How bacteria fight viruses
In the fight to find better treatments for bacterial infections, one rapidly evolving therapy is a group of viruses called bacteriophages (phages). Phages can attack and kill dangerous bacteria while leaving human cells unharmed and bypassing antibiotic resistance.
But bacteria have their own defenses against viruses, and learning how these immune defenses work can help researchers develop better disease-fighting viruses.
Now, new research has revealed that bacteria detect viruses when a viral enzyme cuts an important sensor molecule in the bacterium, kicking off the immune response. The discovery paves the way for development of better phage therapies that can evade the bacterial immune system.
“This is one of the most common forms of bacterial immunity, so when we finally figured it out, it was a total eureka moment,” says the first author on a paper.
The results are published in Science.
One part of the bacterial immune system, called CBASS, leads to a “last resort” immune response that kills the bacterium before viruses can spread to its neighbors. With such a dire consequence for the bacterium, precise sensing of the viral trigger is a necessity.
The sensing mechanism detects a molecule that the virus needs to survive, the author found. “Certain kinds of phages have a protein called a protease, which degrades other proteins,” the author explains. “We found that the protease from the phage actually acts directly on the host protein, and that is the signal that turns on the whole signaling pathway.”
It’s a very different trigger mechanism than what’s found in related antiviral immune pathways, which are activated by the presence of viral genetic material. “This is a totally new mechanism for how these host proteins are activated,” the author says. “I never would have guessed that this was the way it was going to work.”
The author adds that understanding Cyclic oligonucleotide–based antiphage signaling systems (CBASS) may also advance our knowledge of the human immune system. In CBASS, cGAS/DncV-like nucleotidyl transferase (CD-NTase) enzymes sense phage infection and synthesize nucleotide signals to initiate antiviral defense. CBASS is related to a similar immune pathway in humans, indicating that this pathway has persisted at least since bacteria and humans had a common ancestor. And because bacteria have such a rapid life cycle, scientists can use them to very quickly answer questions about how the immune system works, which they can then test in models closer to people.
The authors show that phage prohead proteases directly activate CBASS in vivo, explaining how immunity is initiated late during infection. Structure-based phylogenetic analyses identified activation loops in clade A, D, and G CD-NTases and define residues controlling recognition of distinct phage families.
“The fact that these systems are conserved between bacteria and humans suggests that they've been maintained in these different organisms for that entire evolutionary trajectory,” the author says. “The cells are telling us that this is a really important pathway because they've maintained it for billions of years. It’s incredibly fascinating, and it's a cool window into what's important in maintaining the ability to fight viruses.”
