Latest UMBC-led research in Frontiers in Microbiology suggests that viruses are using information from their environment to “determine” when to take a seat tight inside their hosts and when to multiply and burst out, killing the host cell. The work has implications for antiviral drug development.

A virus’s ability to sense its environment, including elements produced by its host, adds “one other layer of complexity to the viral-host interaction,” says Ivan Erill, professor of biological sciences and senior creator on the brand new paper. Straight away, viruses are exploiting that ability to their profit. But in the longer term, he says, “we could exploit it to their detriment.”

Not a coincidence

The brand new study focused on bacteriophages-;viruses that infect bacteria, often referred to easily as “phages.” The phages within 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 once they generate these appendages. The brand new paper shows that many appendage-dependent phages have patterns of their DNA where the CtrA protein can attach, called binding sites. A phage having a binding site for a protein produced by its host is unusual, Erill says.

Much more surprising, Erill and the paper’s first creator Elia Mascolo, a Ph.D. student in Erill’s lab, found through detailed genomic evaluation that these binding sites weren’t unique to a single phage, or perhaps a single group of phages. Many differing kinds of phages had CtrA binding sites-;but all of them required their hosts to have pili and/or flagella to contaminate them. It couldn’t be a coincidence, they decided.

The power to watch CtrA levels “has been invented multiple times throughout evolution by different phages that infect different bacteria,” Erill says. When distantly related species show the same trait, it’s called convergent evolution-;and it indicates that the trait is unquestionably useful.

Timing is every thing

One other wrinkle within the story: The primary phage by which the research team identified CtrA binding sites infects a selected group of bacteria called Caulobacterales. Caulobacterales are an especially well-studied group of bacteria, because they exist in two forms: a “swarmer” form that swims around freely, and a “stalked” form that attaches to a surface. The swarmers have pili/flagella, and the stalks don’t. In these bacteria, CtrA also regulates the cell cycle, determining whether a cell will divide evenly into two more of the identical cell type, or divide asymmetrically to provide one swarmer and one stalk cell.

Since the phages can only infect swarmer cells, it’s of their best interest only to burst out of their host when there are a lot of swarmer cells available to contaminate. Generally, Caulobacterales live in nutrient-poor environments, and so they are very opened up. “But once they find a great pocket of microhabitat, they develop into stalked cells and proliferate,” Erill says, eventually producing large quantities of swarmer cells.

So, “We hypothesize the phages are monitoring CtrA levels, which go up and down in the course of the life cycle of the cells, to work out when the swarmer cell is becoming a stalk cell and becoming a factory of swarmers,” Erill says, “and at that time, they burst the cell, because there are going to be many swarmers nearby to contaminate.”

Listening in

Unfortunately, the tactic to prove this hypothesis is labor-intensive and intensely difficult, in order that wasn’t a part of this latest paper-;although Erill and colleagues hope to tackle that query in the longer term. Nonetheless, the research team sees no other plausible explanation for the proliferation of CtrA binding sites on so many various phages, all of which require pili/flagella to contaminate their hosts. Much more interesting, they note, are the implications for viruses that infect other organisms-;even humans.

“Every thing that we learn about phages, each evolutionary strategy they’ve developed, has been shown to translate to viruses that infect plants and animals,” he says. “It’s almost a given. So if phages are listening in on their hosts, the viruses that affect humans are sure to be doing the identical.”

There are a couple of other documented examples of phages monitoring their environment in interesting ways, but none include so many various phages employing the identical strategy against so many bacterial hosts.

This latest research is the “first broad scope demonstration that phages are listening in on what is going on on within the cell, on this case, when it comes to cell development,” Erill says. But more examples are on the way in which, he predicts. Already, members of his lab have began searching for receptors for other bacterial regulatory molecules in phages, he says-;and so they’re finding them.

Latest therapeutic avenues

The important thing takeaway from this research is that “the virus is using cellular intel to make decisions,” Erill says, “and if it’s happening in bacteria, it’s almost definitely happening in plants and animals, because if it’s an evolutionary strategy that is sensible, evolution will discover it and exploit it.”

For instance, to optimize its strategy for survival and replication, an animal virus might need to know what type of tissue it’s in, or how robust the host’s immune response is to its infection. While it may be unsettling to take into consideration all the data viruses could gather and possibly use to make us sicker, these discoveries also open up avenues for brand spanking new therapies.

“If you happen to are developing an antiviral drug, and you realize the virus is listening in on a selected signal, then possibly you’ll be able to idiot the virus,” Erill says. That is several steps away, nevertheless. For now, “We are only starting to understand how actively viruses have eyes on us-;how they’re monitoring what is going on on around them and making decisions based on that,” Erill says. “It’s fascinating.”

Source:

University of Maryland Baltimore County

Journal reference:

10.3389/fmicb.2022.918015