New research led by UMBC in Frontiers in Microbiology It indicates that viruses use information from their environment to “decide” when to sit tightly inside their host and when to reproduce and explode, killing the host cell. The work has implications for the development of antiviral drugs.
The virus’s ability to sense its environment, including elements produced by its host, adds “another layer of complexity to the viral interaction with the host,” says Evan Earl, professor of biological sciences and senior author of the new research paper. Currently, viruses are exploiting this ability to their advantage. But in the future, he says, “we can exploit that to their detriment.”
It’s no accident
The new study focused on phages – viruses that infect bacteria, often referred to simply as “phages”. The phages in the study can only infect their hosts when bacterial cells have special appendages, called filaments and flagella, which help the bacteria move and mate. The bacteria produce a protein called CtrA that controls when these polyps form. The new paper shows that many appendice-dependent phages have patterns in their DNA where the CtrA protein can cleave, called binding sites. It is unusual for a phage to have a binding site for a protein produced by its host, Earl says.
Even more surprisingly, Earl and paper first author Elia Mascolo, Ph.D. A student in Earl’s lab, he found through detailed genomic analysis that these binding sites were not unique to a single phage, or even a single group of phages. Many different types of phages contain CtrA-binding sites—but they all required their hosts to have pili and/or flagella to infect them. They decided it could not be a coincidence.
The ability to monitor CtrA levels “was invented many times during evolution by different phages that infect different bacteria,” says Earl. When distantly related species show a similar trait, it is called convergent evolution – and it indicates that the trait is definitely beneficial.
Timing is everything
Another wrinkle in the story: The first hiatus in which the research team identified CtrA-binding sites that infect a specific group of bacteria called Caulobacterales. Caulobacterales are a well-studied group of bacteria, because they exist in two forms: a “swarm” form that swims freely, and a “stalker” form that sticks to the surface. The swarms have bristles/whiplashes, and the stems do not. In these bacteria, CtrA also regulates the cell cycle, determining whether a cell will divide equally into two other cells of the same cell type, or divide asymmetrically to produce one swarm and one stem cell.
Since phages can only infect swarm cells, it is only in their interest to erupt from their host when there are many swarm cells available for infection. In general, Caulobacterales live in nutrient-poor environments, and are highly prevalent. “But when they find a good pocket of micro-habitat, they turn into stalk cells and multiply,” says Earl, eventually producing large amounts of swarming cells.
So, “we assume that phages monitor CtrA levels, which rise and fall over the life cycle of the cells, to see when a swarm cell becomes a stalk cell and becomes a swarm factory,” says Earl, “and at that point, they’ve blown up the cell, because there will be many swarms.” close to injury.
Unfortunately, the method to prove this hypothesis is very labor intensive and difficult, so this was not part of this latest research paper – although Earl and colleagues hope to address this question in the future. However, the research team sees no other plausible explanation for the replication of CtrA-binding sites on many different phages, all of which require the filament/ flagella to infect their hosts. Even more intriguing, they noted, are the implications for viruses that infect other organisms – even humans.
“Everything we know about phages, every evolutionary strategy they’ve developed, has been shown to translate into viruses that infect plants and animals,” he says. “It’s almost taken for granted. So if phages are listening to their hosts, viruses that infect humans are bound to do the same.”
There are a few other documented examples of phages that monitor their environment in interesting ways, but not many different phages that use the same strategy against many bacterial hosts.
This new research is “the first large-scale demonstration that phages listen for what’s going on in the cell, in this case, in relation to cell evolution,” Earl says. But he expects more examples on the way. Already, members of his lab have begun looking for receptors for other bacterial regulatory molecules in phages, he says — and they are finding them.
New treatment methods
A key finding from this research, Earl says, is that “a virus uses cellular intelligence to make decisions, and if it occurs in bacteria, it almost certainly occurs in plants and animals, because if it’s a logical evolutionary strategy, evolution will detect and exploit it.”
For example, to improve its strategy of survival and reproduction, an animal virus may want to know what type of tissue it is in, or how strong the host’s immune response to infection is. While it can be disconcerting to think about all the information viruses can collect and possibly use to make us sicker, these discoveries also open up avenues for new treatments.
“If you’re developing an antiviral drug, and you know the virus is listening for a certain signal, you can probably trick the virus,” Earl says. This is a few steps away, though. Right now, Earl says, “We’re just beginning to realize how effectively viruses focus on us — how they monitor what’s going on around them and make decisions based on that.” “It’s a great.”