Gene + virus + injury = disease?

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.

Cross section of colon tissue from a
patient with Crohn's disease
Image:Nephron via Wikimedia Commons

"Environmental genomic issues are tough to crack," said linkurl:John Mordes,;http://www.umassmed.edu/igp/faculty/mordes.cfm 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 linkurl:Thaddeus Stappenbeck;http://ddrcc.wustl.edu/FACULTY/Stappenbeck.html and virologist linkurl:Herbert Virgin;http://dbbs.wustl.edu/dbbs/website.nsf/FA/492AFD94078E6ABF86256D4E005B2DE6 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 linkurl:paper;http://www.cell.com/fulltext/S0092-8674(10)00545-3 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 linkurl:Richard Blumberg,;http://rsblumberg.bwh.harvard.edu/ 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." To explore this further, Stappenbeck and his team compared gene expression in mutant versus normal mice that are either infected or uninfected with the norovirus. They found that, when exposed to CR6 norovirus, the same set of genes that are down-regulated in normal mice are up-regulated in the mutant mice. As a result, in mutants, the Paneth cells are unable to secrete antimicrobial proteins -- leaving the microbe population in the gut unchecked. In this perturbed state, an additional disruption of the intestinal tract could result in chaos. This is precisely what happened when the mutant mice with the viral infection were fed the toxic chemical, dextran sodium sulfate. This additional "environmental hit," which basically pokes holes into the intestinal lining, set off a cascade of events that resulted in a full-blown inflammatory bowel disease that displayed many of the hallmarks of human Crohn's disease. "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. What's more, Stappenbeck found that by treating the mice with a wide spectrum of antibiotics -- in effect killing the intestinal microbes -- the disease state was eliminated. "This is a virally triggered [disease] that can be treated with antibiotics, which I think is really interesting," Stappenbeck said. "Normally viruses aren't susceptible to antibiotics, but because this [disease], which is triggered by a virus, requires the presence of normal microbes in the gut, you can stop it by wiping them out." The next step, Stappenbeck said, is to determine if there are human viruses that can trigger Crohn's. If so, it would explain why 50 percent of people with European ancestry carry the faulty __ATG16L1__ gene, but only a small fraction are affected. It might also explain why sometimes animal models carrying human susceptibility genes, but without their triggers, don't develop the disease. The paper "sort of opens a Pandora's box that makes interrogating the gene-environment interactions in this and other complex diseases much more complex," Blumberg said. K. Cadwell, et al., "Virus-Plus-Susceptibility Gene Interaction Determines Crohn's Disease Gene Atg16L1 Phenotypes in Intestine," Cell, 141:1135-45, 2010
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[16th October 2009]