Frontiers in Microbiology which has binding sites for CtrA, a protein produced by the bacteriophage host that regulates the production of pili and flagella. The presence of these binding sites only in phages that require their host cells to have pili/flagella to infect them suggests that the phage is monitoring the presence of this protein in order to “decide” whether to stay or replicate and leave its host cell. Credit: Tagide deCarvalho/UMBC” width=”699″ height=”530″/> A delta bacteriophage, the first identified in a new study a Frontiers in microbiology have binding sites for CtrA, a protein produced by the bacteriophage host that regulates the production of pili and flagella. The presence of these binding sites only in phages that require their host cells to have pili/flagella to infect them suggests that the phage is monitoring the presence of this protein to “decide” whether to stay or replicate and leave its host cell. Credit: Tagide deCarvalho/UMBC
A delta bacteriophage, the first identified in a new study a Frontiers in microbiology have binding sites for CtrA, a protein produced by the bacteriophage host that regulates the production of pili and flagella. The presence of these binding sites only in phages that require their host cells to have pili/flagella to infect them suggests that the phage is monitoring the presence of this protein to “decide” whether to stay or replicate and leave its host cell. Credit: Tagide deCarvalho/UMBC
New research led by UMBC a Frontiers in microbiology suggests that viruses are using information from their environment to “decide” when to stay inside their hosts and when to multiply and burst, killing the host cell. The work has implications for the development of antiviral drugs.
The ability of a virus to sense its environment, including elements produced by its host, adds “another layer of complexity to the viral-host interaction,” says Ivan Erill, professor of biological sciences and lead author of the new paper. Right now, viruses are exploiting this ability to their advantage. But in the future, he says, “we could exploit it to their detriment.”
It’s 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 and mate. The bacteria produce a protein called CtrA that controls when they generate these appendages. The new paper shows that many appendage-dependent phages have patterns in their DNA where the CtrA protein can bind, called binding sites. A phage that has a binding site for a protein produced by its host is unusual, Erill says.
Even more surprising, Erill and the paper’s first author, Elia Mascolo, Ph.D. student in Erill’s lab, found through detailed genomic analysis that these binding sites were not unique to a single phage, or even to a single group of phages. Many different types of phages had CtrA binding sites, but all required their hosts to have pili and/or flagella to infect them. It couldn’t be a coincidence, they decided.
The ability to control CtrA levels “has been invented several times throughout evolution by different phages infecting different bacteria,” says Erill. When distantly related species show a similar trait, it is called convergent evolution, and indicates that the trait is definitely useful.
Timing is everything
Another wrinkle in the story: The first phage in which the research team identified CtrA binding sites infects a particular group of bacteria called Caulobacterales. Caulobacterals are a particularly well-studied group of bacteria, because they exist in two forms: a “swarmer” form that swims freely, and a “sticky” form that adheres to a surface. Swarmers have pili/flagella, and stems do not. In these bacteria, CtrA also regulates the cell cycle, determining whether a cell will divide evenly into two more of the same type of cell, or whether it will divide asymmetrically to produce a swarmer cell and a stalk.
Since phages can only infect swarming cells, it is in their best interest to only exit their host when there are many swarming cells available to infect. Caulobacterales generally live in nutrient-poor environments and are widespread. “But when they find a good pocket of microhabitat, they become stuck cells and proliferate,” says Erill, eventually producing large numbers of swarming cells.
So, “We hypothesize that the phages are monitoring CtrA levels, which rise and fall during the cell’s life cycle, to figure out when the swarmer cell is turning into a stem cell and it becomes a swarmer factory,” Erill says, “and at that point, they burst the cell, because there’s going to be a lot of swarmers around to infect.”
Unfortunately, the method to prove this hypothesis is very laborious and extremely difficult, so it was not part of this latest paper, although Erill and his colleagues hope to address this question in the future. However, the research team sees no other plausible explanation for the proliferation of CtrA binding sites in so many different phages, all of which require pili/flagella to infect their hosts. Even more interesting, they point out, 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 are bound to do the same.”
There are a few other documented examples of phages controlling their environment in interesting ways, but none involving so many different phages using the same strategy against so many bacterial hosts.
This new research is the “first large-scale demonstration that phages listen to what’s going on in the cell, in this case, in terms of cell development,” says Erill. But more examples are on the way, he predicts. Members of his lab have already begun looking for receptors for other bacterial regulatory molecules on phages, he says, and are finding them.
New therapeutic pathways
The key conclusion of this research is that “the virus uses cellular intelligence to make decisions,” says Erill, “and if it’s happening in bacteria, it’s almost certainly happening in plants and animals, because if it’s an evolutionary strategy that makes sense, evolution will discover and exploit it.”
For example, to optimize its survival and replication strategy, an animal virus might want to know what kind of tissue it is in or how robust the host’s immune response to its infection is. While it can be unsettling to think about all the information that viruses could gather and potentially use to make us sicker, these discoveries also pave the way for new therapies.
“If you’re developing an antiviral drug and you know that the virus listens to a particular signal, you might be able to trick the virus,” says Erill. That’s a few steps, though. For now, “We’re just starting to realize how viruses have their eyes on us, how they’re monitoring what’s going on around them and making decisions based on that,” says Erill. “It’s fascinating.”
Some microbes wait until their unknowing hosts give them the signal to start multiplying and killing them.
Elia Mascolo et al, The transcriptional regulator CtrA controls gene expression in Alphaproteobacteria phages: evidence for a lytic deferral pathway, Frontiers in microbiology (2022). DOI: 10.3389/fmicb.2022.918015
Provided by the University of Maryland Baltimore County
Summons: New research finds viruses may have ‘eyes and ears’ on us (2022, September 23) Retrieved September 24, 2022, from https://phys.org/news/2022-09-viruses-eyes- ears.html
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