Mice that carry a gene variant earlier linked to the inflammatory bowel disorder known as Crohn's disease only succumb to symptoms if they've also been infected by a common virus, according to a study reported in the June 25th issue of the journal Cell, a Cell Press publication.
The findings offer an explanation for what appears to be a fairly general and perplexing phenomenon: that common gene variants can be tied to infrequent severe disease, the researchers say. It might also explain why mice carrying mutations in human disease susceptibility genes do not always spontaneously reproduce the symptoms of disease. In the past, scientists had often chocked those discrepancies up to inherent differences between mice and men.
The research team led by Thaddeus Stappenbeck and Herbert Virgin of Washington University School of Medicine in St. Louis made the discovery by accident. "This was definitely serendipity," Stappenbeck said.
Two years ago the researchers showed that mice carrying an ATG16L1 gene variant that had been associated with Crohn's diease in humans develop strikingly similar abnormalities in immune cells of the gut known as Paneth cells.
They later placed mice carrying the disease variant in a facility with an "enhanced barrier" to keep out viruses. The animals bedding, cages, food and water were all sterilized under heat and pressure before use and the mice were routinely screened for viral infections.
"In the first mice we looked at [in the enhanced barrier], their gut phenotype was gone," Stappenbeck said. "We had not realized that the virus was a key piece of the puzzle."
When mice raised in the enhanced barrier facility were exposed to a common norovirus known as MNV, they developed symptoms consistent with Crohn's disease within seven days.
While the idea that autoimmune and other diseases might be influenced by viral infections has been around, "this is the first really clear indication of a disease caused by a susceptibility gene and a specific virus," Stappenbeck said. "That's what caught our attention."
The ATG16L1 disease variant in question is found in about half of all people of European descent. But it is just one of more than 30 genes that appear to have some association with Crohn's disease, and it only raises an individual's risk of developing the disease by two-fold. The new findings in mice might explain why that is.
The researchers report that the virus-plus-susceptibility gene interaction generated abnormalities in the gut and a unique pattern of gene activity in Paneth cells. The symptoms were prevented in animals treated with broad spectrum antibiotics.
The findings support what the researchers call a combinatorial view of complex disease, in which the reproduction of the complete set of disease symptoms depends on a combination of specific variants of multiple genes together with particular environmental factors. Under this view, Crohn's disease and other complex conditions might be more aptly described as collections of related but partially distinct diseases.
"It is worth noting that not all Crohn's disease patients exhibit identical symptoms or pathologies, and the nature of Crohn's disease varies over time even within one individual," the researchers write. "In addition, therapeutic interventions that improve conditions for some do not always alleviate disease in others. Therefore, complex diseases may represent a combinatorial confluence of pathologic responses, each with overlapping but nonidentical genetic and environmental causes and therefore therapeutic responses."
The picture that emerges has profound implications for the way scientists view the relationship between genes, environment and health or disease. It also suggests a need to take a much closer look at any underlying viral infections in patients with other chronic diseases, such as diabetes and multiple sclerosis, which have also been linked to common genetic variants.
"We propose that studies examining associations between disease susceptibility and genetic variation should consider the history and current status of viral infections in the individuals," the researchers said. "Similarly, studies examining the correlation between viral infections and disease would benefit from sorting individuals based on genetic background. If we can improve our knowledge in this area, the concept of personalized medicines may come closer to clinical application."
The researchers include Ken Cadwell, Washington University School of Medicine, St. Louis, MO; Khushbu K. Patel, Washington University School of Medicine, St. Louis, MO; Nicole S. Maloney, Washington University School of Medicine, St. Louis, MO; Ta-Chiang Liu, Washington University School of Medicine, St. Louis, MO; Aylwin C.Y. Ng, Massachusetts General Hospital, Harvard Medical School, Boston, MA, Broad Institute of MIT and Harvard, Cambridge, MA; Chad E. Storer, Pfizer Global Research and Development, St. Louis, MO; Richard D. Head, Pfizer Global Research and Development, St. Louis, MO; Ramnik Xavier, Massachusetts General Hospital, Harvard Medical School, Boston, MA, Broad Institute of MIT and Harvard, Cambridge, MA; Thaddeus S. Stappenbeck, Washington University School of Medicine, St. Louis, MO; and Herbert W. Virgin, Washington University School of Medicine, St. Louis, MO, Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, St. Louis, MO.