Recipe for Disease: A Gene and a Virus

Many of us carry genes for diseases that we'll never get. Take Crohn's disease, an autoimmune disorder that attacks the digestive system: Well over half the population harbors at least one genetic variant linked to Crohn's, but just a fraction of them currently have it. Scientists have known for a long time that environmental triggers help explain this discrepancy, but they don't know exactly how. Now, a chance discovery in mice shows that when animals with a particular Crohn's gene are exposed to a specific virus, they develop features similar to those in people with the disease—the first time scientists have noted that genes and environment have intersected in this way in Crohn's. Scientists hope that the finding is just the beginning of many that will show how genes and environment combine in specific ways to produce all sorts of chronic diseases.

The finding was a lucky break. Immunologist Thaddeus Stappenbeck and virologist Herbert Virgin of Washington University School of Medicine in St. Louis were moving their mouse colony to a superclean facility to keep the animals free of viruses that often afflict lab mice. The duo and colleagues had been working with mice who carried a gene called ATG16L1, which raises the risk of Crohn's disease in people. When the mice were moved, they no longer showed abnormalities in their intestinal cells. "There has to be an environmental trigger present in one facility but not the other," Virgin says he thought at the time.

The researchers immediately homed in on a suspect: a virus that Virgin had discovered and reported in Nature 7 years ago called murine norovirus. Noroviruses are common in people, too, for whom they cause gastrointestinal upset. One of the most famous is the Norwalk virus, which commonly sickens people in close quarters, such as on cruise ships. For years, gastroenterologists have noticed that patients coming to them with newly diagnosed Crohn's disease had often suffered some sort of stomach virus recently.

To test whether murine norovirus, which wasn't present in the "clean" facility, could explain the difference in their mice, the researchers infected the ATG16L1 mice with a particular strain of murine norovirus, called MNV CR6. After 7 days, inflammation showed up in a type of intestinal cell called Paneth cells—the same abnormalities the mice had carried in their earlier, more germ-laden home. The inflammation is very similar to what's seen in patients with Crohn's disease in these same cells. Another strain of norovirus didn't have this effect, and the ATG16L1 mice stayed healthy.

Scientists have long believed that in addition to genetics and viral exposure, Crohn's disease is driven partly by an abnormal balance of bacteria in the gut. Virgin, Stappenbeck, and their colleagues approximated this by taking ATG16L1 mice that had already been exposed to the norovirus—so they were destined to suffer some intestinal problems—and fed them a solution that injures the intestines further. In otherwise healthy mice, the solution induced ulcers, which was expected. In the affected mice, the injection led to even more features that looked like Crohn's, including inflammation through the wall of the colon, the team reports in tomorrow's issue of Cell.

R. Balfour Sartor, a gastroenterologist at the University of North Carolina, Chapel Hill, and chief medical adviser to the Crohn's and Colitis Foundation of America in New York City, says the work could help explain why the majority of people who have genes for Crohn's don't develop the disease. It shows that many factors are necessary to induce Crohn's, he says, but not one is sufficient all on its own.

Still, much work remains to be done to determine how applicable the findings are to people, says Sartor. He'd also like to know whether other viruses, in the presence of ATG16L1, can have the same effect—and whether other Crohn's genes combined with this norovirus do, too.

Stappenbeck says that another big mystery is the mechanism—how exactly this norovirus combines with this particular gene to produce gut abnormalities. He and Virgin also plan to start looking at humans with Crohn's disease to see what viruses they may have been exposed to.