The Subtle Art of Viral Espionage: Understanding How Eavesdropping Viruses Engage in Battle to Infect Hosts

A team of scientists spearheaded by Bonnie Bassler from Princeton University has unearthed the fact that a myriad of viruses can detect and respond to bacterial chemical signals. This ability helps them decide when to switch from a latent state to an aggressive one. This widely adopted mechanism has been confirmed, with the tools that manage it and the subsequent behaviors of virus-infected cells being identified and observed via advanced imaging techniques.

Bassler and her team discovered that a wide array of viruses react to quorum sensing and other chemical signals produced by bacteria.

Viruses essentially have two modes of operation, akin to villains in films: they can remain dormant and stealthily bypass body defenses or launch an all-out offensive. When launching an attack, they break out and fire in all directions, often destroying the host cell they’ve been inhabiting. The success of the attack hinges on the presence of enough healthy cells nearby to continue the infection. If the viral particles hit nothing, the virus becomes non-functional.

Deciding when to switch from a dormant state to an aggressive one is thus a crucial choice for a virus.

Around four years ago, Princeton biologist Bonnie Bassler and her then-graduate student Justin Silpe uncovered that one particular virus had an edge: it could intercept the communication among bacteria. Specifically, it listened for the “We have a quorum!” chemical that bacterial cells release when they’ve achieved a crucial mass.

Now, Bassler, Silpe, and their fellow researchers have identified that numerous viruses react to quorum sensing or other bacterial chemical signals. This study was recently published in the Nature journal.

Bassler, the Squibb Professor in Molecular Biology and the head of the molecular biology department at Princeton, said, “The world is teeming with viruses that can surveil suitable host information. We are yet to fully understand all the stimuli, but we’ve demonstrated in this paper that this is a common mechanism.”

They not only illustrated the prevalence of this strategy but also discovered tools that manage it and signal the viruses to switch from the dormant state to the aggressive one.

Viruses that target bacterial cells, known as bacteriophages — or phages, can infect a bacterium at the same time if they’re all in a dormant mode, known as lysogeny. When this involves multiple phages residing in a single bacterium, it’s called polylysogeny.

Despite their peaceful coexistence in the bacterium, the phages have a fragile truce that lasts until something triggers one or more of them to switch to an aggressive mode.

Researchers studying phage warfare had long known that significant disruptions to the system — like high-dose UV radiation, carcinogenic chemicals, or certain chemotherapy drugs — can provoke all resident phages into aggressive mode.

However, the findings of Bassler’s team are different.

Using high-resolution imaging, postdoctoral research associate Grace Johnson observed individual bacterial cells infected with two phages while exposing them to a universal trigger signal.

The unexpected result was that instead of having a clear winner, some bacteria were producing both phages simultaneously. “No one ever imagined that there would be three subpopulations,” stated Bassler.

The next challenge was to find a way to activate only one of the two phages at a time.

Silpe, who had returned to Bassler’s lab as a postdoctoral research associate after his postdoctoral studies at Harvard, spearheaded the effort to find the triggers. While they still don’t understand what signals these phages respond to in nature, Silpe has developed a unique artificial chemical trigger for each phage.

When Silpe exposed the polylysogenic cells to his trigger, only the responding phage replicated, leaving the other phage completely dormant. “I didn’t think it would work,” he admitted. “I expected both phages to replicate since my strategy didn’t imitate the natural process, so it was a surprise to see only one phage replicate.”

Bassler noted that this was a first, “Bacteria are really tiny. It’s challenging to image even individual bacteria, let alone phage genes inside bacteria. We’re talking about something smaller than small.”

Johnson had been modifying the imaging platform for another quorum-sensing project but realized that it could reveal secrets about Silpe’s eavesdropping phages.

Bassler emphasized the importance of their findings, “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.”

The research was funded by Princeton University, Howard Hughes Medical Institute, the National Institutes of Health, the National Science Foundation, the Jane Coffin Childs Memorial Fund for Medical Research, the Office of Extramural Research, and the Damon Runyon Cancer Research Foundation.

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• Princeton University
• Howard Hughes Medical Institute
• National Institutes of Health
• National Science Foundation
• Jane Coffin Childs Memorial Fund for Medical Research
• Office of Extramural Research
• Damon Runyon Cancer Research Foundation