Until a few years ago, biologists did not know that bacteria have their own immune system. It was known that most bacteria are killed by invading viruses, called bacteriophages, and it wasn’t a stretch to imagine that bacteria had developed some way of combating the attacks, but the details of such an immune system were unknown. A team of scientists led by researchers at the University of Georgia (USA) have made some important discoveries about the mechanisms by which bacteria defend themselves.
The viruses that attack bacteria (phages) work by invading the bacterial cell with forms of viral RNA or DNA. Once inside the cell, the viral material typically takes over the bacterial protein production, in effect fooling it, to produce viral rather than bacterial proteins. Some phages, called lysogenic, incorporate themselves within the cell and may become dormant until environmental conditions are right for activity. Others phages, called lysic, immediately (that is, within minutes) produce so much material that the bacterial cell breaks open (lyses) and releases new phages to infect still more cells. The key to this process is the ability of phage RNA or DNA to match with the receptors on bacterial DNA or RNA. This is where the bacterial immune system operates.
“Understanding how bacteria defend themselves gives us important information that can be used to weaken bacteria that are harmful and strengthen bacteria that are helpful,” said Michael Terns, a professor of biochemistry and molecular biology in UGA’s Franklin College of Arts and Sciences. “We also hope to exploit this knowledge to develop new tools to speed research on microorganisms.”
The system, whose mechanism of action was uncovered in the Terns lab (Michael and Rebecca Terns are a husband-wife team), involves a “dynamic duo” made up of a bacterial RNA that recognizes and physically attaches itself to a viral target molecule, and partner proteins that cut up the target, thereby “silencing” the would-be cell killer.
The invader surveillance component of the dynamic duo (an RNA with a viral recognition sequence) comes from sites in the genomes of bacteria and archaea, known technically as “clustered regularly interspaced short palindromic repeats” or more familiarly called CRISPRs. (A palindrome is a word or sentence that reads the same forward and backward.) CRISPR RNAs don’t work alone in fighting invaders, though.
Their partners in invader defense are Cas proteins that arise from a suite of genes called “CRISPR-associated” or Cas genes. Together, they form the “CRISPR-Cas system,” and the new paper describes this dynamic duo and how they protect bacteria from viruses.
“You can look at one as a police dog that tracks down and latches onto an invader, and the other as a police officer that follows along and `silences’ the offender,” said Rebecca Terns. “It functions like our own immune system, constantly watching for and neutralizing intruders. But the surveillance is done by tiny CRISPR RNAs rather than antibodies.”
What the team discovered was that a particular complex of CRISPR RNAs and a subset of the Cas proteins termed the RAMP module recognizes and destroys invader RNAs that it encounters.
This study reports in some detail how the biochemistry of phage DNA/RNA is detected by bacteria and then cut into harmless segments. They note that there are some interesting parallels between the bacterial immune system and that of more complex organisms, even humans. Much of the underlying chemical processes are similar, however, the bacterial system involves simpler biochemical pathways.
This seminal research will stimulate much new work to understand and eventually manipulate the bacterial immune process. However, there are many steps between this study and the actual control of bacterial processes. This means years of exploratory laboratory work and then more years in (hopefully) developing useful applications.