Defining Reovirus Strain-Specific Differences That Trigger Inflammation to Dietary Antigen in the Development of Celiac Disease

Abstract

Celiac disease is an immune-mediated intestinal disorder that occurs in genetically predisposed individuals exposed to dietary gluten. Viral infections are associated with the induction of celiac disease. However, not all viruses confer disease susceptibility, and little is known about specific viral characteristics that dictate immunopathologic outcomes. Feeding mice ovalbumin (OVA) as a model antigen results in systemic tolerance to OVA, which is marked by induction of regulatory T cells (Tregs) and absence of OVA-specific inflammatory T (TH1) cells. Peroral inoculation with reovirus strain T1L abrogates oral tolerance to OVA, as evidenced by a reduction in Tregs and promotion of OVA-specific TH1 cells, whereas inoculation with strain T3D-RV does not. Relative to infection with T3D-RV, T1L infection is associated with increased levels of inflammatory cytokines including type 1 interferons and interferon regulatory factor-1, which are required for virus-induced tolerance blockade. Compared to T3D-RV, T1L induces less activation of caspase-3, less sloughing of intestinal villi, and prolonged infection. To examine the relationship between apoptosis and infection in the intestine, a panel of T1L x T3D-RV reassortant viruses was recovered. The reassortant viruses capable of suppressing apoptosis in the intestine also displayed enhanced infection capacity, similar to T1L. These findings suggest that viral strains inducing minimal levels of apoptosis are capable of producing high titers of virus, which in turn may be required to stimulate the inflammatory signals required to break immunological tolerance to food antigens.