gene + virus + injury = disease?

The Scientist | One of the most detailed studies to date of how the interaction between genes and environment results in disease has demonstrated that an inflammatory bowel disease resembling human Crohn's needs a specific mutation, virus, and injury to develop in mice.

"Environmental genomic issues are tough to crack," said John Mordes, professor of endocrinology at the University of Massachusetts, who has previously characterized a gene-virus interaction in type1 diabetes. "This is a significant contribution to the evolving understanding of how the environment interacts with genomic predisposition."

The team, led by immunologist Thaddeus Stappenbeck and virologist Herbert Virgin of Washington University School of Medicine, found that the diseased state was brought about by the complex interplay among a mutation in an autophagy-related gene called ATG16L1, a specific virus, a toxic substance, microbes in the rodent's gut, and the rodent's own immune response. The findings appear in a paper that will be published tomorrow in Cell.

"It's a well-documented scientific example of how very particular environmental events and genes interact to result in disease," said Richard Blumberg, chief of gastroenterology at Brigham and Women's Hospital at Harvard Medical School, who was not involved in the study.

The researchers stumbled upon this discovery by accident. Two years ago, they had succeeded in describing how a mutation in mouse ATG16L1 wreaked havoc in a type of cell that inhabits the lining of the small intestine. These so-called Paneth cells are involved in mucosal immunity and secrete antimicrobial proteins. But in mice that carry the mutation, the cells grow abnormally and malfunction, similar to what's observed in human Crohn's patients with mutations in the same gene.

But then, in early 2009, the mutant mouse colonies with the abnormal Paneth cells were moved to a new super-sterile facility. To the researchers' surprise, the mutant mice that grew up in the new facility had normal-looking, healthy Paneth cells. It was as if the mice didn't carry the mutation at all. This led them to believe that something other than genetics was at play.

Enter the murine norovirus -- a family of small, RNA viruses discovered by Virgin in 2003. The viruses are practically found in almost all mouse facilities except the new one, which was designed expressly to keep them out.

Sure enough, when the researchers fed mutant mice different viral strains, they found that after exposure to one strain known as CR6, the Paneth cells transformed from healthy to abnormal.

This goes back to what doctors have observed for years. "It is not uncommon to find that inflammatory bowel disease follows some sort of gastric infection in a clinical setting," Stappenbeck explained. "So the connection between the disease and an infectious process has been around for a while."

"So really there were three environmental factors that were working together with the mutation: the viral infection, the composition of the microbiota (presumably induced by the viral infection), and a very specific inflammatory hit on the [intestinal lining]," Blumberg said.