Virus-mediated Loss of Oral Tolerance and Celiac Disease

Viral infections can cause complex autoimmune and inflammatory disorders. Celiac Disease (CD) is an important disease model sharing many features with autoimmune disorders such as type-1 diabetes. CD is a unique model because antigen and HLA association are known, and the tissue is easily accessible. CD is also an important health problem induced by dietary gluten that is increasing in prevalence. The common denominator for CD is loss of oral tolerance (LOT) to gluten. Using humanized transgenic mice overexpressing IL-15 in the lamina propria, the Jabri lab recently identified IL-15 as a key mediator of CD pathogenesis promoting LOT. However, more than 50% of CD patients have normal levels of IL-15 expression, suggesting that alternative pathways can lead to LOT. Interestingly, these patients display abnormally high levels of type-1 Interferons (IFNs). Because type-1 IFNs are frequently produced in response to viral infections we hypothesize that gut-associated viruses contribute to CD induction thereby constituting an alternative pathway to IL-15. We will test this hypothesis and determine whether an avirulent pathogen cleared from the infected host can nonetheless promote LOT by disrupting intestinal immune homeostasis without causing tissue damage. This research will establish the concept that immunopathology can develop despite or because of effective protective anti-viral immunity. Aim 1: Define mechanisms underlying LOT during reovirus infection using OVA as model antigen. Identify viral determinants of LOT. Furthermore, using type-1-IFN receptor deficient mice we will determine how defects in type-1 IFN signaling influence reovirus-mediated immunopathology. We will investigate viral cell tropisms, assess anti-reovirus immune responses, and define mucosal immune alterations associated with LOT. Aim 2: Elucidate how reovirus infection impacts on CD pathogenesis. We will assess the capacity of reovirus infection to induce CD-like pathology. Furthermore, a discovery-based subaim has been developed to identify new networks involved in LOT and to define virus-induced LOT transcriptional signatures. For these experiments, we will use integrated functional and genomic approaches and mouse and human models that mirror each other. The outlined research activity will enhance an understanding of the pathological functions of viruses and type-1 IFNs in the mucosal immune system and allow us to define how interactions between viruses, type-1 IFNs, and the host influence the response to luminal antigens and the risk of developing complex autoimmune and inflammatory disorders. This topic is highly relevant, as intestinal viral infections are implicated in CD, IBD, and other autoimmune illnesses. This research will identify novel pathways in CD pathogenesis and establish a conceptual framework for the development of new preventive and therapeutic approaches for CD and other autoimmune diseases. The proposed project will combine immunology, virology, chemistry and systems biology in cooperation with Dr. Dermody (Vanderbilt University), Dr. Xavier (Broad Institute) and Dr. Khosla (Stanford University).

Celiac disease is a complex-multifactorial disorder arising from gluten ingestion, a protein found in wheat, rye and barley. Celiac disease is also an important health problem that is increasing in prevalence. As with most complex-multifactorial disorders, celiac disease is the result of the interplay between genetic factors, environmental factors such as gluten and other unknown parameters that cooperate to induce an immune-mediated response that results in small intestinal damages typically found in celiac patients. Certain virus strains, capable of infecting the gastrointestinal tract, such as rotavirus or reovirus, have been associated with an increased incidence of celiac disease and other autoimmune disorders in several studies. In the course of my FWF funded Erwin Schrödinger Fellowship at the University of Chicago, I was investigating the mechanisms through which viral infections, in particular gastrointestinal viruses such as reovirus, can contribute to the inflammatory responses in the small intestine occurring in celiac disease patients. Analysis of serum and small intestinal biopsies of celiac disease and control patients revealed that celiac disease patients show a significant increase in reovirus antibodies in the serum that correlated with virus-associated markers in small intestinal biopsies suggesting that celiac disease patients had more severe, chronic or recent infections. The small intestine is an important intersection, where ingested food components, the gut microbiota and other microbes get into contact with the bodys own cells and tissue. Because the majority of those extrinsic factors do not pose a threat to the body, the immune system in the gut has evolved to be tightly controlled to avoid triggering unnecessary immune responses. This is in part accomplished by the abundant presence of regulatory T-lymphocytes in the gut that suppress inflammatory responses, a mechanism known as oral tolerance. However, using mice as an experimental model-organism, we could demonstrate that certain viral infections could shift the regulatory gut T-lymphocyte population towards a proinflammatory T-lymphocyte phenotype resulting in the imbalance of the gut immune system and subsequent loss of oral tolerance. Furthermore, in our genetically modified celiac-disease-mouse model we could show that reovirus infections of the small intestine and simultaneous ingestion of gluten led to similar clinical symptoms when compared with celiac disease patients. We therefore propose that certain viral infections could have an important contribution in the development of celiac disease. Finally, our demonstration that specific viral infections are strongly associated with celiac disease development, allows us to promote early vaccination against gastrointestinal viruses to reduce the incidence of celiac disease in defined at- risk populations (e.g. family members of celiac disease patients).