For single-celled organisms, bacteria are surprisingly chatty.
Though they’re often thought of as solitary, bacteria spend a decent bit of time engaging in conversation. But they don’t use words; instead, these microscopic creatures shoot chemical cues into their environment. When many bacteria are in close proximity, these signals can reach a high enough density to prompt complex, cooperative group behavior.
Banding together, bacteria can raise collective defenses, enhance access to resources, and even cause serious infections. This collaborative decision-making process is called quorum sensing, and it comes in different flavors: Some bacteria collude only with their own kind, while others will speak with other species. But outside the bacterial kingdom, these bugs keep mum. Their chemical code is one that no living creature—aside from a human researcher—has ever been able to crack.
The key word here, however, is “living.” Today, in the journal Cell, a team of researchers unmasks an unexpected decrypter of the dialect of quorum sensing: A bacteria-hunting virus called a bacteriophage, or phage for short.
By learning the lexicon of bacteria in the Vibrio genus—including those that cause cholera—a polyglot phage called VP882 effectively wiretaps the conversations of its microbial prey, which might allow the virus to attack when its target population is at its densest. Genetically manipulating the building blocks of this system could someday equip researchers and clinicians with tools to treat bacterial disease—all inspired by the covert ops of these viral eavesdroppers.
“This is really beautiful phage biology,” says Fitnat Yildiz, a microbiologist who studies Vibrio bacteria at the University of California, Santa Cruz but did not participate in the new research. “This is an elegant example of how phage can take a [bacterial] regulatory network and use it to their own advantage.”
But phages aren’t the only ones listening in. Study author Bonnie Bassler, a microbiologist at Princeton University, may be humanity’s most fluent ambassador to the world of quorum sensing. Years of research from her team have deciphered some of the most important facets of this bacterial vernacular. Just last year, a team from Bassler's lab, including graduate student Justin Silpe, discovered that bacteria in the Vibrio group are capable of detecting a molecular signal called DPO. In the world of quorum sensing, when it’s loud, there’s a crowd—and blasting DPO allows microbes to announce themselves to others. A single blip means virtually nothing, but a whole slew of DPO messages indicates the presence of a mob. A swarm of microbes can then take this cue to act in concert.
Through chemicals like DPO, bacteria are constantly chattering in the world around us—but we humans never hear a thing. The system functions like a radio station, in that effective communication requires a signal and a receiver. A tower can ping out all the waves it wants, but only those with the right technology can tune in to the message.
That’s no issue for bacteria: All Vibrio species make DPO’s “receiver”—a protein called VqmA. But Silpe was eager to find who else might be privy to the discourse. While searching for versions of VqmA across the kingdoms of life, Silpe noticed an anomaly on his list that wasn’t alive at all: A Vibrio-infecting virus.
Both Silpe and Bassler were initially skeptical. “There’s never been a quorum sensing gene on a phage before,” Bassler explains. “Quorum sensing is supposed to be about bacteria communicating.”
And when it comes to code breakers, viruses are especially far outside the line of usual suspects. Technically, they’re not even alive. Viral particles are entirely dependent on living cells, like those of humans or bacteria, to replicate and persist. But the viral modus operandi is undoubtedly a successful one. Bacteriophages alone are the most ubiquitous entities in nature, found wherever their host of choice—bacteria—thrive.
When a phage encounters a bacterial cell, it will inject its own genome into its host. Then, the virus co-opts the bacterium’s molecular machinery to manufacture more of itself. The process destroys the host, releasing a fresh batch of phage to begin the infectious cycle anew.
But the timing of this exit can vary. After infecting a cell, some phages will nestle their genes in next to their host’s, genetically immortalizing the virus. When the bacterium copies its own genome during reproduction, the phage’s gets taken along for the ride. In these cases, only specific cues from the environment, like damage to the host, can awaken the phage from dormancy.
For the phage, coming out of hiding is irreversible, as the process destroys the original host. But if there’s a new crop of susceptible bacteria nearby, the benefits far outweigh the risk. So for VP882, monitoring the availability of prey—say, by encoding its own quorum sensing cipher—might be an incredibly effective strategy.
At first, the possibility seemed ludicrous to the researchers. But Silpe followed his hunch, and was amazed to find that the phage gene didn’t just look like VqmA—it listened like it, too. When Vibrios in its vicinity sent out DPO dispatches, VP882 took notice. And if the messages amassed, the phage jolted awake and broke loose from the cell.
Because more DPO means more bacteria—and, thus, more potential hosts—adding VqmA to its repertoire might be a way for a phage to time a mass exodus, Bassler explains. Though this idea awaits confirmation, Bassler thinks the virus might be using Vibrio’s own secret language against itself. It’s an “insidious and fantastic” tactic, she says.
“This is remarkable,” says Asma Hatoum-Aslan, a microbiologist studying bacteria-phage interactions at the University of Alabama who did not contribute to the study. “This shows that this kind of phage, even in the host cell, is clearly not dormant. It’s listening. It’s still interacting with the environment on some level.”
The surprising crosstalk between such different entities also illuminates the widespread nature of communication—in even its simplest forms. “Viruses don’t carry much genetics around with them, but they actually have a lot of autonomy,” says Paul Turner, a phage biologist at Yale University who did not contribute to the study. Phages are dependent on cellular life to propagate, but by turning an ear to their hosts, he says, “they’re still encoded to decide their own fate.”
For Silpe and Bassler, this is only the beginning. This may be the first phage that’s officially recognized for learning the quorum sensing lingo, but the researchers think VP882 is unlikely to be alone.
“Phages were discovered over a century ago,” says Rotem Sorek, a microbiologist who studies bacteriophages at the Weizmann Institute of Science in Israel but did not contribute to the study. “The foundations of microbiology came from phages. And still, after all these years, we are still finding very surprising and new features of phage biology.”
The researchers have already begun to brainstorm therapeutic applications of this unusual system. One potential avenue might be a riff on phage therapy, wherein bacteriophages can be deployed to selectively kill disease-causing bacteria. VP882 naturally targets bacteria of the Vibrio genus, including cholera-causing Vibrio cholerae. This phage could be engineered to function as something of a Trojan horse, Silpe says, delivering a molecular self-destruct button to dense populations of Vibrio without damaging, say, the important gut microbes that live within a human host. Turner compares the technique to “taking a scalpel and cutting something unwanted out of a complex community.”
Such a system would involve harnessing the power of a natural system derived from phage-microbe interactions—not unlike CRISPR, Turner says. “We’re figuring out what’s evolved in the microbial world and appreciating its elegance,” he explains. “But now we can also think about using these tools to solve human problems.”
Editor's Note, December 25, 2018: This article has been updated to clarify the role of Justin Silpe in the discovery of the quorum sensing molecule, DPO.