New UMBC-led research in Frontiers in microbiology suggests that viruses use information from their environment to “decide” when to sit inside their hosts and when to multiply and burst, killing the host cell. The work has implications for the development of antiviral drugs.
A virus’s ability to sense its environment, including things produced by its host, adds “another layer of complexity to the virus-host interaction”, says Ivan Erill, professor of biological sciences and lead author of the new paper. . Currently, viruses exploit this ability to their advantage. But in the future, he says, “we could exploit it to their detriment.”
Not a coincidence
The new study focused on bacteriophages -; viruses that infect bacteria, often simply called “phages”. The phages in the study can only infect their hosts when the bacterial cells have special appendages, called pili and flagella, that help the bacteria move around and mate. Bacteria produce a protein called CtrA that controls when they generate these appendages. The new paper shows that many appendage-dependent phages have motifs in their DNA where the CtrA protein can attach, called binding sites. A phage with a binding site for a protein produced by its host is unusual, Erill says.
Even more surprisingly, Erill and the diary’s first author Elia Mascolo, a Ph.D. student in Erill’s lab, discovered 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 phage had CtrA binding sites, but they all required their hosts to have pili and/or flagella to infect them. It couldn’t be a coincidence, they decided.
The ability to monitor CtrA levels “has been invented many times throughout evolution by different phages infecting different bacteria,” Erill says. When distant species show a similar trait, it’s called convergent evolution – and it indicates that the trait is definitely useful.
Timing is everything
Another twist in the story: The first phage in which the research team identified CtrA binding sites infects a particular group of bacteria called Caulobacterales. Caulobacteria are a particularly well-studied group of bacteria, as they exist in two forms: a “swarming” form that swims freely and a “stalked” form that attaches to a surface. Swarms have pili/flagella, and stalks do not. In these bacteria, CtrA also regulates the cell cycle, determining whether a cell will divide evenly into two other cells of the same type, or divide asymmetrically to produce a swarm cell and a stem cell.
Since phages can only infect swarm cells, it is in their interest to only exit their host when there are many swarm cells available to infect. Generally, Caulobacterales live in nutrient-poor environments and are widely dispersed. “But when they find a good pocket of microhabitat, they become stalked cells and proliferate,” Erill says, eventually producing large amounts of swarming cells.
Thus, “We hypothesize that phages monitor CtrA levels, which rise and fall during the cell life cycle, to determine when the swarm cell becomes a stem cell and becomes a swarm factory,” Erill says, “ and at that time they burst the cell, because there will be many swarms nearby to infect.”
Unfortunately, the method for proving this hypothesis is labor intensive and extremely difficult, so it was not part of this last article, although Erill and his colleagues hope to address this issue in the future. However, the research team sees no other plausible explanation for the proliferation of CtrA binding sites on so many different phages, all of which require pili/flagella to infect their hosts. Even more interesting, they note, 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 a given. So if phages listen to their hosts, viruses that affect humans will do the same.”
There are a few other documented examples of phages surveying their environment in interesting ways, but none include so many different phages employing the same strategy against so many bacterial hosts.
This new research is the “first large-scale demonstration that phages are listening to what is happening in the cell, in this case, in terms of cell development,” Erill said. But more examples are on the way, he predicts. Already, members of his lab have started looking for receptors for other bacterial regulatory molecules in phages, he says, and they are finding them.
New therapeutic avenues
The main conclusion of this research is that “the virus uses cellular information to make decisions,” says Erill, “and if that happens in bacteria, it almost certainly happens in plants and animals, because if it This is an evolutionary strategy that makes sense, evolution will find out and exploit it.”
For example, to optimize its survival and replication strategy, an animal virus may want to know what type of tissue it is found in or how robust the host’s immune response to its infection is. While it might be unsettling to think of all the information viruses could gather and possibly use to make us sicker, these findings also point the way to new therapies.
“If you’re developing an antiviral drug and you know the virus is listening for a particular signal, maybe you can trick the virus,” Erill says. It’s a short walk, though. For now, “we are only just beginning to realize how actively viruses are watching us; how they monitor what’s going on around them and make decisions based on that,” Erill says. “It’s fascinating.”
University of Maryland Baltimore County