Eavesdropping viruses: The unseen war within our cells

In a recent study, scientists at Princeton University have unveiled a complex battle that takes place within the microscopic world of bacteria. This battle is waged between eavesdropping viruses known as bacteriophages (or phages) and the bacteria they seek to infect.

Viruses, in their quest to replicate, can adopt one of two strategies: either they remain hidden within the host, stealthily replicating without causing harm, or they mount a full-scale attack, bursting forth from the host cell and seeking to infect others. 

The latter strategy is often a suicide mission, as the virus destroys the very cell it depends on. For a virus, the decision of when to shift from this “chill mode” into “kill mode” is crucial for its survival.

Eavesdropping viruses

In 2019, Princeton biologist Bonnie Bassler and her then-graduate student Justin Silpe made a remarkable discovery. They found that one particular virus had a unique advantage: it could “eavesdrop” on the communication between bacterial cells, listening in for a chemical signal known as the “We have a quorum!” message. This process, termed quorum sensing, allows bacteria to communicate when they have reached a critical number. This discovery was an award-winning breakthrough.

“The world is loaded with viruses that can surveil appropriate host information,” explains Bassler. “We don’t know what all the stimuli are, but we showed in this paper that this is a common mechanism.”

Switching to kill mode

In the world of bacteriophages, the strategy isn’t simple. Phages can infect a bacterium simultaneously, coexisting peacefully while the cell continues to replicate, a state known as polylysogeny. This is no peaceful cohabitation; rather, it’s a state of mutually assured destruction, waiting for a trigger to switch into kill mode. High-dose UV radiation, chemicals, and even some drugs can be that trigger.

Yet, Bassler’s team found something unexpected. Through the use of high-resolution imaging, postdoctoral research associate Grace Johnson was able to watch individual bacterial cells infected with two phages. When she activated a universal kill signal, she saw not a clear winner, but three subpopulations of bacteria, each responding differently to the phages.

“No one ever imagined that there would be three subpopulations,” said Bassler. “That was a really exciting day,” added Johnson.

Manipulating viruses 

The team sought a way to trigger only one of the two phages at a time, and Silpe found the triggers. When he exposed the cells to his specific cue, only the targeted phage replicated.

“I didn’t think it would work,” he confessed. “I expected that because my strategy did not mimic the authentic process found in nature, both phages would replicate. It was a surprise that we saw only one phage. No one had ever done that before, that I’m aware of.”

Warfare inside of a single cell

“I don’t think anybody even thought to ask a question about how phage-phage warfare plays out in a single cell because they didn’t think they could, until Grace J. and Justin did their experiment,” Bassler said. “Bacteria are really tiny. It’s hard to image even individual bacteria, and it’s really, really hard to image phage genes inside bacteria. We’re talking smaller than small.”

Bassler noted that the majority of the world’s bacteria have more than one phage chilling inside of them, but no one has been able to manipulate and image them her team did.

“The cunning strategy where they could induce one phage, the other phage, or both phages on demand – that was Justin’s coup, and then to be able to actually see it happening in a single cell? That’s also never been done. That was Grace J. We can see the phage warfare at the level of the single cell.”

Implications of the study

But this research goes beyond just observing an extraordinary microscopic war. It opens a window into the largely unexplored realm of viral genes.

“Yes, here, we discovered the functions of a few phage genes, and we showed that their jobs are to enable this completely unexpected chill-kill switch and that the switch dictates which phage wins during phage-phage warfare,” said Bassler. “That discovery suggests there remain potentially even more exciting processes left to find.”

“Phages started the molecular biology era 70 years ago, and they’re coming back into vogue both as therapies and also as this incredible repository of molecular tricks that have been deployed through evolutionary time. It’s a treasure trove, and it’s almost completely unexplored.”

Published in the current issue of Nature, this research could hold the keys to new biological insights and future medical innovations. The story of eavesdropping viruses may have only just begun, but its implications resonate across the vast landscape of biology.

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