Vertebrates like us rely on a complicated, multi-layered immune system to limit the impact of pathogens. Specialized B and T cells play a central role in recognizing specific pathogens and providing a memory of past infections.
Obviously, unicellular organisms such as bacteria and archaea cannot take the same approach. But that doesn’t mean they are helpless. They also have an adaptive defense system that keeps a memory of past infections (and happens to be a great gene editing tool). Now, researchers have discovered that a family of related proteins is used to fight viruses in organisms ranging from bacteria to humans. Although the effects it causes vary between organisms, it appears to be able to recognize a wide range of viruses.
Mammals have a family of immune proteins called STAND (for no small reason) that are part of what is called the innate immune system. This arm of our immune system does not recognize specific pathogens; instead, it recognizes general features of infection, such as molecules found on the surface of most bacteria.
All STAND proteins have a similar structure: a part that recognizes pathogens, a part that binds to an energy-providing molecule called ATP, and a part that allows the protein to trigger a response. As is typical of the innate immune system, these can recognize features specific to an infection, such as parts of the bacterial cell wall or double-stranded RNA. Once they recognize something, the STAND proteins aggregate and trigger a response, such as inflammation, to induce the death of the infected cell.
STAND proteins are so central to immunity that they have been found throughout the animal kingdom, in plants and fungi. The general way we respond to infections appears to have a deep evolutionary history.
what depth The new research is based on the fact that genes that resemble those encoding mammalian STAND proteins appeared in many bacterial genomes, including bacteria known as E.coli i salmonella. So a team of researchers decided to test if they could be operating in the same way.
New organism, similar effect
The researchers showed that adding extra copies of the STAND genes to the bacteria allowed them to resist viral infection more effectively. This worked because the bacteria that were infected died, rather than living long enough to produce new viral particles. This proved to be a useful tool. The researchers added individual virus genes with the STAND genes and looked for the combinations that caused the bacteria to die. Some of the STAND proteins recognized a key component of the virus coat, killing the cell; others recognized the engine that packages the DNA inside the virus.
They then checked the equivalent proteins from a wide range of related viruses and showed that the STAND proteins could recognize most of them. Although all these proteins form a similar structure in three-dimensional space, the individual amino acids in this structure are quite different. Therefore, this suggests that STAND proteins recognize the shape of the structure, which allows them to defend against a wide variety of viruses.
Later work showed that once the viral protein was recognized, the STAND proteins aggregated into groups of four. This activated them as enzymes, at which point they began to digest the double-stranded DNA, which well explained the lethal effect on the bacteria. But this was not the only way to block viral infections. A search through bacterial genomes showed that some chewed up proteins, while others appeared to stay anchored to the cell membrane. Overall, the researchers found 18 different ways in which STAND proteins could inhibit virus activity.
And the proteins seem to work in a wide variety of species. Looking across bacterial and archaeal genomes, about 5 percent of them have some form of the STAND protein.
It’s not all good news
Unfortunately, bacteria aren’t the only ones that evolve. The researchers also checked for viral genes that code for proteins that get in the way of the STAND proteins. And, in news that should disappoint everyone and surprise no one, they were found. So even when the viral genes would normally induce STAND to kill cells, these STAND inhibitors allowed the cells to continue growing. How they manage to block these genes is not clear at this time.
The other big question that remains is how STAND proteins became part of the immune response in such a large range of organisms. One possibility is that they are ancient and have simply been inherited from a common ancestor across all branches of life. But that doesn’t fit the data that well. If you make a tree of STAND proteins based on their relationship, it does not align with the tree of organisms they are in. In other words, if you’re looking for the most closely related STAND protein out there E.coliyou can find it in a bacterium that is not closely related E.coli.
This is a hallmark of horizontal gene transfer, where entire genes are shuffled from one species to another. Therefore, it is also possible that STAND proteins evolved in more complex organisms, but were picked up by bacteria through horizontal gene transfer and then spread further by the same process. At this time, there are no data that allow us to ascertain which of the possible explanations for the widespread distribution of STAND proteins is likely to be the cause.
science2022. DOI: 10.1126/science.abm4096 (About DOI).