A recent paper in the journal, Cell by Cadwell, K. et al entitled “Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine”, eloquently demonstrated in mice the temporal interplay between chronic virus infection, genes linked to Crohn’s disease susceptibility, inflammatory cytokines and presence of intestinal bacteria to contribute to Crohn’s disease pathology.
The notion that environmental factors, including viruses and bacteria can trigger the onset of autoimmune-driven diseases such as type I diabetes, multiple sclerosis and Crohn’s disease in individuals having a certain genetic background is broadly recognized. Identifying which virus or bacteria is the trigger or why some individuals with a given genetic makeup acquire the disease whereas others with the same genetic background remain unaffected is still mystery. (Akerblom et al., 2002; Christensen, 2007; Hanauer, 2006)
Crohn’s disease is an autoimmune disease caused by a chronic bowel inflammation. The disease is characterized by ulceration and inflammation of the small intestine and regions of the colon. Chronic inflammation leads to increased of atrophy of inner intestinal villi, tissue fibrosis, and hypertrophy of intestine smooth muscle and the outer layer nerves of the bowel wall. (Xavier and Podolsky, 2007)
At least 30 genes are associated with an increased risk of Crohn’s disease, including the ATG16L1 gene. (Cooney and Jewell, 2009) ATG16L1 mutants confer less than a 2-fold increase risk in Crohn’s disease susceptibility. The protein that is encoded by the ATG16L1 gene is involved cell autophagy. Autophagy is a tightly-regulated catabolic process found in all eukaryotic cells and through lysomsomal degradation of cellular components regulates cell homeostasis. (Huett et al., 2010) Surprisingly, the authors of the study found only mice that expressed the Atg16L1 mutation and were raised in a typical mouse facility environment displayed autophagy abnormalities that were similar to that found in individuals with Crohn’s disease in their intestinal Paneth cells (Cadwell, 2009). Paneth cells are intestinal epithelial cells important in mucosal immunity. If identical mice were raised in a germ-free environment, they showed no evidence of Paneth cell abnormality. The authors correctly surmised that a strain of norovirus, present in many animal care facilities was the culprit. Norovirus are responsible for the majority of nonbacterial gastroenteritis in humans, an infection most characterized by symptoms of vomiting and diarrhea.(Glass et al., 2009) Cadwell et al (2010) found that when mice were infected with a strain of norovirus strain that established a persistent infection (norovirus strain CR6) long before subsequent expose to a bowl chemical irritant that causes minor intestinal inflammation and ulceration, these mice showed heightened expression of inflammatory cytokines, Tumor necrosis factor (TNF)-a and interferon (IFN)-g , (two cytokines that play an important role in Crohn’s disease progression (Chowers and Allez, 2010; Fuss et al., 1996), and an intestine tissue histology that matched that found in Crohn’s disease. As intestinal bacteria are known to contribute to inflammatory bowel disease (Kang et al., 2008), the investigators also treated the diseased animals with antibiotics. If animals were administrated antibiotics they were devoid of disease, thus linking an important contribution for resident intestinal bacteria in Crohn’s disease progression.
The importance of this study to virologists is that this mouse model provides a clear example of how genetic background in concert with persistent virus infection has to occur first to result in an irrevocably change in how the immune system will later respond to more immediate disease triggers. This study also suggests that it may be difficult to pin-down a particular viral or bacterial infection trigger as the cause of a given autoimmune-driven disease, as if it may have occurred long before disease manifestation.
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