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Gene, toxin and virus interact in Crohn's disease

5 July 2010
Appeared in BioNews 565

US scientists have shown for the first time how a virus, a toxin and a genetic mutation interact to cause Crohn's disease. The study, in mice, may help explain why many people with disease risk genes don't develop the condition.

The study authors, led by Professors Thaddeus Stappenbeck and Herbert Virgin from the Washington University School of Medicine, made their discovery by accident. They had been studying how a gene mutation can lead to Crohn's-like symptoms in mice through the disruption of so-called 'Paneth cells' that line the small intestine. The normal function of these cells is to release anti-microbial agents that regulate the growth of natural bacterial in the gut.

However, when their study was moved to a new sterile facility, the mice grown there were completely healthy, despite having the genetic mutation. After further investigation, a mouse strain of the norovirus - a sickness virus commonly found in traditional animal houses but absent from the new sterile facility - was implicated. When the apparently healthy mice were fed the virus, the Paneth cells became abnormal and the intestinal symptoms re-emerged

The infected mice were then fed a toxic chemical known to perforate the gut and went on to develop a full blown inflammatory bowel disease similar to Crohn's disease.

Gene expression studies showed the genetic mutation causes the Paneth cells to respond differently to infection by the norovirus. Mice without the genetic mutation saw decreased expression of certain genes when they were infected by the virus. Expression of the same genes increased, however, in mice carrying the genetic mutation.

This affected their ability to release anti-microbial agents to control the bacteria in the gut meaning that, when the gut sustained an injury - as simulated by the toxin - the unregulated bacteria spread, leading to inflammatory bowel disease.

When the infected mice were treated with antibiotics (killing the bacteria), the symptoms went away.

'We've provided a very specific example of a virus triggering a complex disease - if the mice don't have the virus, they don't get the symptoms', said Professor Virgin. 'Many viruses infect nearly 100 percent of people, and when their genes interact with our genes, they may be contributing to such diseases'.

Professor Richard Blumberg, from Harvard Medical School, said that this study 'sort of opens a Pandora's box that makes interrogating the gene-environment interactions in this and other complex diseases much more complex'.

The study is published in Cell.

Gene + virus + injury = disease?
The Scientist (blog) |  24 June 2010
Mouse Disease Needs Gene plus Viral Infection
Scientific American |  24 June 2010
Recipe for Disease: A Gene and a Virus
Science magazine |  24 June 2010
Virus gene interaction triggers Crohn like pathology in mouse model
Medscape Today |  29 June 2010
Virus works with gene to cause Crohns like illness
EurekAlert |  24 June 2010
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