Justin Silpe and Bonnie BasslerDenise Applewhite

When bacteria talk, Bonnie Bassler listens. She just never figured that viruses were listening, too.

Since the 1990s, the Princeton University biologist has been studying a phenomenon called quorum sensing, in which bacteria release molecules that indicate how many of their peers are around. Through these messages, they can coordinate their behavior and launch certain actions—such as infectious attacks—only when their numbers are large enough.

Bassler’s student Justin Silpe has now discovered that a virus can listen in on these signals, for sinister ends. The virus in question is a phage—a spidery thing that infects and kills bacteria. Once it infects its host, it has two modes: wait or kill. If it chooses the latter, it makes multitudes of daughter viruses that fatally burst through the host bacterium, ready to infect others. But what if there are no others around? “If you’re a virus, if you don’t get into another host, you’re doomed,” says Bassler.

As Silpe found, the phage avoids this fate by detecting the same quorum-sensing signals that the bacteria use to gauge their numbers. It can effectively wait for its hosts to announce that they’re plentiful, so that when it kills one, its progeny will assuredly find many more. “It’s so cunning to eavesdrop on a quorum-sensing molecule,” says Bassler. “No one has seen that before.”

Quorum sensing was already a revolutionary concept. As Bassler uncovered its details over decades, she and others were shocked to realize that supposedly simple organisms such as bacteria could communicate and coordinate. But viruses are even simpler. They’re not even technically alive! They’re entirely different entities from bacteria, yet they are intercepting and interpreting the same molecular messages. It’s like a rock eavesdropping on a bird.

The seeds of this discovery were planted a few years ago, when Bassler’s team identified a new kind of quorum-sensing system in Vibrio cholerae, the bacterium that causes cholera. It secretes a signaling molecule called DPO, which it detects using a protein called VqmA.

When the bacteria start to infect a host, there aren’t many of them around, and the DPO signals they produce drift off into the ether. But as their numbers swell, the signals become more concentrated and start landing on the VqmA detectors. When this happens, it triggers a sequence of genes that reprogram the bacteria, turning off their ability to infect and turning on their ability to disperse. This is partly why “cholera is such an insidious disease,” says Bassler. Through quorum sensing, Vibrio cholerae can wait until the time is right, before “getting out of the host by the gazillions to infect the next host.”

By searching through online databases, Silpe showed that many closely related Vibrio bacteria also have detectors that resemble VqmA. But so, apparently, did a virus—a phage called VP882, which some Taiwanese researchers had found from a marine Vibrio a decade ago. Was that a random coincidence? A mistake in the database? Or, as Silpe suggested, could the virus somehow be tapping into the messages of its hosts? “I thought, We’re going to waste a lot of time on this, because it’s a crazy mistake,” says Bassler, cheerfully. “But that’s what we do.”

The researchers who found the VP882 virus had retired, but not before putting a sample of the host bacteria in a repository. It took six months for Silpe to track down that precious sample, and fortunately, those bacteria still had some virus inside them.

Through careful experiments, Silpe showed that his hunch was right: The virus’s version of VqmA can indeed detect the same DPO signals that the bacteria release. And when it does, it prompts the virus, which usually lies harmlessly in wait, to start killing its host. “There’s a funny logic to it,” says Bassler. “At high densities, cholera, a parasite, wants to leave its host and get into another host. And at high densities, the virus, a parasite of a parasite, wants to leave its host and get into another host. They’re doing the same thing [using the same signal molecule].”

The virus isn’t just eavesdropping either. Remember how the cholera bacterium uses its VqmA detector to shift from infection to dispersal. Silpe found that the virus’s version of VqmA can launch the same genetic program, forcing its bacterial host to disperse. “The phage, while it’s preparing to kill cholera, is also messing with hundreds of bacterial genes,” Bassler says. Perhaps that’s all part of the same strategy: The phage not only ensures that its progeny have plenty of hosts to infect, but also ensures that those hosts spread far and wide.

VP882 has another odd quality: Unlike most phages, which are limited to specific hosts, it can infect a wide range of bacteria. It only listens to the messages exchanged by Vibrios, but Silpe managed to engineer it to eavesdrop on other species, including Salmonella and E. coli. And when it detects molecules that are present only in its targets, it kills them. This random virus is now a programmable assassin that Silpe can set to go after particular targets. “It was like a gift from evolution to us,” says Bassler.

For decades, scientists have tried to use phages to treat bacterial diseases, and these phage therapies are especially promising now that many bacteria have evolved to resist traditional antibiotics. But there’s a catch: Phages are usually finicky in their hosts, so researchers would need to find a different virus for every bacterial infection they want to treat.

Silpe’s work offers an alternative strategy. “They propose using a promiscuous phage that can infect many different bacterial species, but will only kill in response to a predefined cue,” says Adair Borges, who studies phages at the University of California, Santa Francisco. “It’s an interesting new take on phage therapy [that] allows for even more specificity and control over the bacteria that are killed.”

“This isn’t a phage therapy yet,” Bassler cautions. She and Silpe have only tested their programmed phages in test tubes, and it falls to other researchers to see whether the same approach could work in the clinic. They’re more interested in learning more about how phages work in nature, and they note that researchers have long underestimated these viruses. Last year, for example, another group, led by Rotem Sorek from the Weizmann Institute of Science, discovered that some phages have their own version of quorum sensing, trading messages that tell them when to kill their hosts.

“These are inanimate, non-living viruses,” says Bassler. “There’s something beautiful about how ancient communication is.”

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