Science Editor

The question of whether it is genetics or environmental factors that determines health is increasingly being recognized as irrelevant. In all but the simplest of cases, disease results from an interaction between the two.

In the June 24, 2010, edition of Cell, researchers provided a striking example of such an interaction. In this case it is a three-way interaction that, at least in mice, leads to Crohn's disease. Animals with a risk gene plus a specific viral infection develop Crohn's-like symptoms in response to a harmful chemical. The authors wrote in their paper that their experiments "may help explain why many people with disease risk genes do not actually develop disease."

Crohn's disease is an inflammatory autoimmune disease; it is not fatal, but can require lifelong medication and surgery. Genomewide association studies have uncovered several risk genes for Crohn's; among them is the gene Atg16L1. Clearly, however, Crohn's sufferers need something besides the risk-conferring variant of Atg16L1 to actually develop the disease. The frequency of the risk conferring allele in the population is about 50 percent, meaning that about a third of the population can be expected to be homozygous for the high-risk allele. The vast majority of them never develop Crohn's.

The serendipitous discovery was made in the course of the team's work on Paneth cells, a type of cells that help regulate gut microbes and are abnormal in mice with Atg16L1 mutations.

As part of their work, the authors moved such mice into a norovirus-free facility. But co-corresponding author Thaddeus Stappenbeck told BioWorld Today, "to our surprise, when we transferred them, we lost the phenotype."

"Connecting the dots" happened pretty quickly once Stappenbeck and his colleagues realized that mice with the risk gene in a murine norovirus-free facility lack the usual problems with their Paneth cells.

But, he said "Beforehand? We had no idea."

The particular virus Stappenbeck and his team identified is mouse-specific – murine norovirus. But there are human noroviruses responsible for many outbreaks of gastroenteritis or stomach flu, particularly where people are in close quarters. "You hear about them on cruise ships," Stappenbeck said.

The move had been undertaken in order to be able to engineer and work with immunodeficient animals, not because of a hunch that a viral infection was involved in Crohn's.

Stappenbeck, who is at Washington University in St. Louis' Digestive Diseases Core Research Center, and his colleagues went on to test how expression patterns changed in Atg16L1-mutant mice after infection with norovirus, and found that a number of genes involved in intracellular protein traffic, protein targeting and localization, and amino acid metabolism were affected.

Paneth cells with the combination of virus plus susceptibility gene also showed a strongly altered response to a cellular toxin, dextran sodium sulfate, that is used to induce gastrointestinal injuries for research purposes. In mice with the virus/risk gene combination, exposure to dextran sodium sulfate led to symptoms that resemble Crohn's. This response was dependent on the cytokines TNF-alpha and IFN-gamma, as well as commensal bacteria that colonize the gut.

Given that the studies published in Cell were serendipitous, and indicated that the timing details of viral infection matter greatly to whether disease will develop, the idea of building on the studies to tease out contributors to other complex diseases seems somewhat daunting. But Stappenbeck believes there are general lessons to be learned from the work.

One lesson, he said, is that to identify "you will need correlates in manipulable systems" – in other words, mouse models.

Obviously, however, it will also be necessary to make sure those manipulable systems aren't the only ones that show the interaction.

"The big idea going forward is to start sequencing human samples" – an effort his team is currently undertaking, but that will "take a while" to bear fruit. By themselves, the mice prove nothing. "But they tell us where to look," he said, "which will hopefully pay off."

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