Viruses pull a lot of dirty tricks to dodge our immune defenses and make us sick, but now scientists have come up with a trick of their own. Researchers have discovered that prompting cells to combat bacteria can also help them fight off viruses, even though the cells presumably wouldn’t have the right weapons to do so. “This would be analogous to, in a football game, arming the defense with baseball bats,” says Andrew Gewirtz, a mucosal immunologist at Georgia State University in Atlanta. The finding could solve a vaccine mystery, as well as lead to new ways to combat infectious diseases.

Your cells don’t respond the same way to bacteria and viruses. They switch on different genes and release different mixtures of chemical messengers and protective molecules. That’s why Gewirtz and his colleagues were taken aback by the results of an experiment they performed 6 years ago. The researchers were testing whether an injection of flagellin, a protein that’s part of the tails (or flagella) some bacteria use to propel themselves, activates the body’s antibacterial defenses. Their findings showed that it did, enabling mice to subsequently survive what should have been a lethal dose of harmful intestinal bacteria.

The surprise came when Gewirtz’s team infected the mice with rotavirus, a common cause of severe diarrhea in young children. Even though the virus doesn’t have a flagellum, injecting the rodents with flagellin in advance protected them against the pathogen.

In their new study, published online today in Science, Gewirtz and his colleagues figured out why. The researchers determined which two pathogen-sensing molecules enable cells to recognize the injected flagellin. When the cells detect flagellin, they spur other cells to emit interleukin-22 (IL-22) and interleukin-18 (IL-18), molecular signals that help orchestrate a defensive response. That presumably would help kill off bacterial invaders, but why does it work against viruses?

The answer may lie in the habits of the rotavirus, which invades cells lining the small intestine. IL-22 makes intestinal cells more resistant to viral invasion, whereas IL-18 thwarts the virus by spurring cells it has already infected to commit suicide. So when these molecules are activated, they fight bacteria as well as rotavirus. Indeed, injecting mice with IL-22 and IL-18 triggered the same antiviral effect as flagellin, the team found.

Gewirtz says that this mechanism might work because “it’s not what the virus is used to.” Rotavirus evolved to evade the body’s antiviral defenses, but it can’t counteract the response activated by flagellin or the combination of IL-22 and IL-18.

“It’s a very nicely documented story,” says Roger Glass, a rotavirologist at the National Institutes of Health in Bethesda, Maryland. “They work through all possible explanations.” The crossover protection the authors observed is unexpected because the opposite often occurs, says immunologist and physician Robert Sabat of Charité University Medicine Berlin. For example, viral lung infections often leave patients more vulnerable to bacterial infections, not less.

Glass adds that the results might solve a mystery about the two new oral rotavirus vaccines introduced within the last decade. The vaccines contain weakened forms of the virus and are much more effective in developed countries than in developing countries, where rotavirus kills more than 400,000 children every year. Children in developing countries have probably been exposed to more flagella-carrying bacteria when they are vaccinated, he says. As a result, their cells might destroy the rotaviruses in the vaccine before they can develop immunity.

Researchers don’t expect the discovery to have much impact on global mortality from rotavirus infections. Treating children with IL-22 and IL-18 wouldn’t be feasible in developing countries where the virus is a major killer because of their limited medical facilities, Glass says. In developed countries, though, the combination might benefit children and adults whose immune systems are impaired because of cancer treatment or diseases like AIDS and who are vulnerable to rotavirus infections.

Sabat notes that researchers have already completed some clinical trials of IL-22 and IL-18 in cancer patients, and IL-18 did cause side effects such as fever, nausea, and difficulty breathing. However, he says, “a combination of IL-22 and low-dose IL-18 might be well tolerated.”

IL-22 and IL-18 might have other uses as well. “We think the system we’ve developed will be broadly applicable to other viral infections,” Gewirtz says. He and his colleagues are now testing whether the combination allows mice to resist a range of viruses, including norovirus, a gastrointestinal pathogen notorious for causing outbreaks on cruise ships.