In the early experiments it looked like the virus called VP882 was doing something that should be impossible for a thing that is not a bacterium, and not technically even alive: intercepting molecular messages exchanged by its host bacteria, and reading them to determine the best time to annihilate the whole bacterial colony. “As scientists, this is just unimaginable to us,” says Bonnie Bassler, a molecular biologist at Princeton University. “We were delighted and skeptical at the same time. It was almost too good to be true.”
Not only did it turn out to be true for VP882; Bassler learned there is a family of bacteria-infecting viruses (a subgroup of a kind called bacteriophages, or just “phages”) that eavesdrop on their hosts’ routine molecular communications with other bacteria. That means VP882’s kill trigger could be easily manipulated to target any bacteria, Bassler says—opening the possibility that the virus could be engineered into an ideal killing machine for dangerous pathogens.
In 2009 scientists in Taiwan first found VP882 in a bacterium related to cholera. The bacterium “probably made someone sick,” Bassler says, and in investigating the illness, “researchers came across the virus. They sequenced it and dropped it in a [DNA] repository.” When Bassler’s graduate student Justin Silpe came across the virus in that database, he had been looking for a gene that encodes a receptor for a particular molecule called DPO. Cholera and related bacteria utilize this molecule for something called “quorum sensing”—a kind of chemical “speech” that bacteria use to figure out how many of their own kind are nearby.
When a host detects a high concentration of quorum-sensing molecules in its environment, it is as if the bacteria are hearing a high volume of chatter in a room. “This tells them they have enough neighbors around to do collective behavior”—such as causing disease—Bassler says. She and Silpe had hoped to find the DPO receptor in other kinds of bacteria than cholera. Instead, it showed up in VP882. “Quorum sensing is supposed to be about bacteria. But here it was on a viral genome,” she notes. “We were like, ‘What is that virus doing?’”
When they conducted experiments with VP882, Silpe noticed that when it was in a cholera colony without DPO, the phage and the bacteria coexisted peacefully. But “we clearly noticed that where we added DPO, the cells died,” he says. “That was a clear indication the phage was killing them.” To confirm the quorum-sensing signal was indeed the kill trigger, Silpe mutated the DPO receptor on VP882—and showed the mutated phages did not kill.
This told the duo the virus tunes into the quorum-sensing information and uses it to figure out how many potential victims are around. If the virus senses enough DPO, it means a buffet is nearby; that signals VP882 to start destroying its host bacterium and sending copies of itself careening into the colony. Otherwise VP882 lies quietly and waits for the bacteria to reproduce. “It’s a wonderful and insidious strategy,” Bassler says. “It allows the phage to optimally find its next victim.” The team published their results in Cell Thursday.