Bacteria and the bacteriophages that infect them engage in a never ending evolutionary battle. “Because of this constant warfare, each side has evolved elaborate mechanisms to out the other one,” said Michael Laub, an immunologist at the Massachusetts Institute of Technology.
In a recent paper published in Nature, Laub and his team reported that a phage protein called the major capsid protein induces an abortive infection system, or programmed suicide, by interacting with a bacterial protein called CapRel (1).
CapRel serves in a defense system that protects E.coli against phages. Laub and his team determined the structure of the CapRel protein and found that it consist of two domains: an N-terminal toxin domain and a C-terminal antitoxin domain. The antitoxin domain acts as a phage sensor. When phages are out of sight, the antitoxin domain stops the toxin domain from killing the bacteria.
During phage infections, this antitoxin domain binds to the phage’s major capsid protein. This binding drives a structural change in CapRel that unleashes the toxin domain. When this structural change occurs, the CapRel protein stops protein synthesis in the infected cell. New protein synthesis is vital for both the phage and bacteria to live, and stopping it kills both the bacteria and the phage particles infecting it.
Cell suicide may seem counterintuitive as a defense mechanism, yet bacteria use it to ensure that phages will not continue propagating and infecting other cells. While scientists were aware of this kind of cell death, the mechanism itself was somewhat surprising.
“You could argue it makes sense that [CapRel’s target] is the capsid protein – something the virus has to make and is potentially hard to mutate. But in other regards, capsid proteins are something the phages make relatively late in the infection,” said Laub. Once the phages are making these proteins, it seems too late for the bacteria to act.
According to Joseph Bondy-Denomy, a microbiologist and immunologist from the University of California, San Francisco who was not involved in this study, this defense mechanism shows that “bacterial immunity is sophisticated enough to recognize essential proteins in bacteriophages, killing the cells just a little bit before the phage wants the cells to die.”
While it's possible that the CapRel phage detection mechanism could translate to other bacteria-phage relationships, “it's very possible that this particular mechanism is a minority of CapRel systems, and most of them actually work in a different way,” said Bondy-Denomy. Nevertheless, he said, this “was a pretty careful and deep paper that checks a lot of boxes."
Bacteria-phage arms races have sparked interest in applications such as phage therapies, where scientists use phages to fight against bacterial infections in humans. While the concept is exciting, the success of this therapy is not yet proven. “When [the therapy] doesn’t work, one possibility is that there's a defense system that's blocking the activity of phages,” said Laub.
Understanding the mechanism by which bacteria become resistant to phage will help guide the future use of phage therapies, said Joseph van Belleghem, an immunologist formerly at the University of Zurich who was not involved in this study. “If we can decipher which type of bacteria and which type of phages elicit a certain type of resistance mechanism, we can make educated guesses on which phages to use.”
According to Bondy-Denomy, there are currently only a handful of instances where scientists have shown a direct binding between a bacterial immune protein and phage structural protein. Future discoveries on bacterial immune systems could teach more about eukaryotic immunology. “This is the start of an explosion of antiviral systems that detect structural proteins. There are so many of these systems that are based on small molecule signals. I feel like it's going to lead to new drugs,” said Bondy-Denomy.
Laub and his team are currently looking at CapRels’ ability to defend against other unrelated phages to learn how conserved or different the triggers or activators are in different systems. “There's just a huge number of toxin-antitoxin systems. So, there's a lot to keep us busy,” he said.
- Zhang, T. et al. Direct activation of a bacterial innate immune system by a viral capsid protein. Nature 612, 132–140 (2022).