Like many a cockamamie idea, this one was so crazy, it just might work. In these images, E. coli bacteria harbor proteins from a bacteria-killing virus that can eavesdrop on bacterial communication. At left, one protein from the virus has been tagged with a red marker. At right, the virus has overheard bacterial communication indicating the bacteria have achieved a quorum; it sends its protein to the poles of the cell (yellow dots). Bonnie Bassler and Justin Silpe, Department of Molecular Biology, Princeton University But then again, the Bassler microbiology lab at Princeton University was built on crazy ideas that proved right, like that bacteria talk to one another, says Bonnie Bassler, director of the lab, chair of the Department of Molecular Biology at Princeton and investigator at the Howard Hughes Medical Institute. Of course, they don't speak in so many words. Rather, they communicate with chemical signals, she says — a discovery that helped earn her a MacArthur genius grant in 2002. So when graduate student Justin Silpe proposed that a virus could eavesdrop on those bacterial conversations, Bassler says she initially thought it was a bit wild. "There's never, ever been evidence of a virus listening in on bacterial communication," she says. "But what the heck. It's not my job to shut down people's creativity." Silpe, a researcher in the Bassler Lab, worked on his idea for two years and reported results in the Dec. 13 online edition of the journal Cell. When a virus infects bacteria, it's called a phage. He investigated a phage called VP882. He showed that when VP882 entered salmonella in his experiments, it could sense information emitted from bacteria. Bacterial cells communicate by producing and releasing chemical signal molecules that other bacteria pick up, a process called "quorum sensing." The communication lets them figure out how many other bacteria are in the vicinity, allowing them to act as a group and increase the power of disease-causing bacteria to do damage. So in a way, the virus was "overhearing" bacterial conversations. "It's brilliant," says Nancy Connell, microbial geneticist and a senior scholar at the Johns Hopkins Center for Health Security. She is not connected with the Cell report. "This discovery just blew me away," she says. "I'm a bacterial geneticist, and I think about bacterial communication. But who thought that viruses could perceive anything?" The discovery opens the door for viruses to become infection fighters, perhaps one day joining antibiotics in the medical arsenal to fight against salmonella, E. coli, cholera and other bacterial infections, says Bassler. Silpe's discovery built on previous work in the lab in which researchers discovered a receptor within each bacterial cell for a signal that bacteria use to communicate with one another, he says. Silpe further analyzed thousands of DNA sequences, eventually broadening his search beyond the bacterial domain. That was when he found one receptor that didn't match any bacteria. It was for VP882. "This was unexpected because it was suggesting that there's a virus out there that has kind of joined the bacterial conversation," says Silpe. This one virus had a receptor that previously had only been found on bacteria to facilitate their communication. But unlike bacteria, the virus doesn't take part in the conversation. It just listens. "It can only pick up on a host signal. It can only eavesdrop," he says. Silpe found that the virus uses information overheard from bacterial communication to time its attack on surrounding bacterial cells. Entering other cells is the only way they can survive. What VP882 can overhear is a signal indicating that a large group of similar bacteria is nearby. The signal gets louder as infected cells accumulate, alerting the virus that it's a good time to kill the host bacterial cell, break out, enter other infected cells and go on a bacteria-killing rampage. Timing is everything. When the virus enters the bacterial cell, it has a couple of possible moves. It might just wait until more bacteria have gathered, because to survive, it has to move from one bacterial cell to another. If it replicates itself too soon, it won't be able to find a new host cell. Without a new host, the virus is doomed. By eavesdropping on the communication signal, as VP882 can do, the virus increases the chances that when it replicates and bursts out of the host cell, there will be many neighboring cells to successfully enter and destroy, he says. Silpe initially rewired the VP882 virus to make it attack salmonella on command. The virus could also be re-engineered, he says, to specifically attack other disease-causing bacteria. The unmodified phage did not kill the bacteria. "So we demonstrated that we could target and kill a bacterial species on command," says Bassler. Finding alternative treatments for infectious diseases is crucial, says Connell, because many strains of disease are becoming resistant to antibiotics. "We're entering what's been called the post-antibiotic era," she says. And while it's a long way from a basic science discovery like an eavesdropping virus VP882 to a therapy to treat human disease, says Bassler, this discovery offers a promising avenue of research. "It's a dream that other scientists will take this initial discovery and actually make a treatment that's safe and reliable," she says. "I sure hope somebody does that, but it'll take a long time." Meanwhile, Bassler is awed by the demonstrated need of all living things — down to the tiniest bacterium — to communicate. "Communication is something we see as so sophisticated," she says. "But bacteria do it. And Justin has shown that even viruses do it. You have to think about how ancient the need to communicate is, how it goes across all domains through billions of years of evolution." Source
